Cancer in Dialysis and Transplant Patients

Dialysis patients and kidney transplant recipients have considerably greater cancer risk than the general population. This chapter discusses cancer in dialysis patients and kidney transplant recipients, with the exception of skin malignancies, which are considered separately in Chapter 34 .

Cancer in Dialysis Patients

Soon after the first reports of cancer arising de novo in kidney transplant recipients, it was suggested that dialysis patients were also at heightened risk of cancer. Subsequent reports confirmed that the incidence of malignancy was higher while on dialysis than in the general population. Most early reports were about cancers affecting the renal tract, either directly or indirectly. It is now clear that there is an overall increase in incidence of malignancy in patients with chronic kidney disease (CKD). The first study large enough to study the relationship between cancer, including less common types, estimate small increases in risk, and seek associations with the causes of CKD and modalities of dialysis (hemodialysis or peritoneal dialysis) was by Maisonneuve. This confirmed an overall increased risk of cancer in patients with end-stage kidney disease (ESKD). Generally, the types of cancer were similar to the cancers observed with increased frequency in transplant recipients. Most common were cancers of the urinary tract, but cancers of the tongue, liver, lower genital tract in women, external genitalia in men, and thyroid, lymphomas, and multiple myeloma, had increased incidence.

Cancer Risk in Dialysis Patients

Some of the most comprehensive long-term data on the development of malignancy in dialysis patients and kidney transplant recipients are available from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. This registry has collected information on all patients in Australia and New Zealand who have been treated with dialysis or received a kidney transplant since 1963. Although there are several much larger registries in the world, the population base and completeness of the information recorded sets the ANZDATA registry apart from most others. The 2012 ANZDATA report examined the incidence of cancer in 50,635 patients (with 145,043 person-years of follow-up) treated with dialysis and 17,150 patients (159,413 person-years of follow-up) after a first kidney transplant in Australia and New Zealand, compared with the general population incidence, between 1982 and 2009. Indirect standardization was used, standardizing for differences in age, sex, and calendar year, to calculate standardized incidence ratios (SIR) with their 95% confidence (CIs). SIR can be interpreted as risk ratio, where an SIR value of 1 is risk equal to that of the general population of similar age and sex, living in an equivalent time period in the same country, and an SIR of 2 is double the risk, etc. Comprehensive data on the standardized incidence of cancer in both kidney transplant recipients and dialysis patients treated in other countries have also been reported (summarized in Table 35.1 ) . These estimations demonstrate the remarkable similarities in incidence trends. When considering cancer risk by site it is apparent that the pattern of increased risk is varied. For many cancers, for example cancers of the lung and colon, there is a slight increase in risk among dialysis patients, with a somewhat greater increase after transplantation. For several other cancers, however, the risk increase after transplantation is more marked. Most of these are known or postulated to have a viral etiology; for example, carcinoma of the cervix, lymphoma, and Kaposi’s sarcoma.

Table 35.1

Risk of Cancer After Commencement of Dialysis and After a First Kidney Transplant Across Different Countries

Data from:

Cancer Site	ICD-O	Dialysis Before First Transplant Standardized Incidence Ratio [95% CI]			After First Transplant Standardized Incidence Ratio [95% CI]
Cancer Site	ICD-O	Australia (2012) ^b	United States (2016) ^c	Denmark (2017) ^d	Australia (2012) ^a	United States (2016) ^b	Denmark (2017) ^c
Infection Related
Kaposi’s sarcoma	C46	8.88 [4.62–17.07]	6.4 [2.8–13]		22.29 [15.06–32.98]	55 [44–68]
All lymphoma	C81–85, C96	1.13 [0.91–1.40]			9.64 [8.73–10.66]
Non-Hodgkin’s lymphoma			1.7 [1.5–2]	1.6 [1.2–2.2]		5.9 [5.5–6.3]	6.1 [4.6–8.2]
Hodgkin’s lymphoma			0.87 [0.45–1.5]			3.4 [2.6–4.3]
Liver	C22	2.41 [1.81–3.21]	1.8 [1.5–2.2]		2.80 [1.91–4.12]	1 [0.79–1.3]
Stomach	C16	1.55 [1.22–1.97]	1.4 [1.1–1.7]		1.44 [0.99–2.09]	1.6 [1.3–1.9]
Oropharynx			1.2 [0.88–1.7]			1.3 [0.97–1.7]
Anus			2.6 [1.7–3.8]			4.8 [3.7–6.2]
Uterus	C54–55	1.36 [0.96–1.89]	0.93 [0.72–1.2]		1.69 [1.17–2.45]	0.94 [0.75–1.2]
Cervix	C53	2.81 [1.91–4.13]	0.89 [0.59–1.3]		4.81 [3.58–6.47]	1.1 [0.75–1.5]
Ovary	C56	0.96 [0.60–1.55]			1.22 [0.73–2.07]
Vulva
Penis and male genital	C60, 63	1.40 [0.45–4.35]			10.94 [6.06–19.75]
Other genital sites			3 [2–4.2]			5.1 [4–6.5]
Immune Related
Trachea bronchus lung	C33–34	1.70 [1.53–1.88]			1.76 [1.51–2.06]
Lung ^a			1.2 [1.1–1.3]			1.6 [1.5–1.7]
Melanoma	C43	1.08 [0.88–1.20]	1.5 [1.2–1.8]		2.74 [2.44–3.09]	2.8 [2.5–3.2]
Nonepithelial skin			2.5 [1.5–3.9]			13 [11–15]
Lip	C00	0.13 [0.03–0.05]	3.5 [1.7–6.2]	3.9 [2.0–7.5]		18 [15–22]	12.3 [6.1–24.5]
ESKD-related
Kidney, ureter, urethra	C64–66, 88	5.99 [5.35–6.70]			8.58 [7.52–9.78]
Kidney	C64		9 [8.4–9.6]	2.8 [2.2–3.7]		6.4 [5.9–6.8]	6.9 [5.0–9.6]
Other urinary tract			1.6 [1.3–1.9]			1.9 [1.6–2.2]
Thyroid	C73	4.32 [3.33–5.62]	4 [3.5–4.6]	3 [1.7–5.5]	4.12 [3.13–5.44]	2.9 [2.5–3.4]	4.7 [2.3–9.9]
Multiple myeloma	C90	7.09 [6.12–8.22]	1.8 [1.5–2.2]		2.23 [1.49–3.32]	1.8 [1.4–2.1]
Other
Colorectal	C18–20	1.03 [0.92–1.16]	1.2 [1.1–1.3]		1.44 [0.99–2.09]	1.1 [0.96–1.2]
Pancreas	C25	1.14 [0.86–1.51]	1.1 [0.86–1.4]		1.27 [0.84–1.93]	1.5 [1.3–1.8]
Leukemia	C91–95	1.09 [0.03–1.43]	1.4 [1.1–1.8]		1.81 [1.34–2.46]	1.8 [1.5–2.1]
Prostate ^a	C61	0.58 [0.5–0.66]	0.85 [0.78–0.92]		0.82 [0.68–0.98]	0.92 [0.85–0.98]
Breast ^a	C50	1.28 [1.11–1.47]	1.2 [1–1.3]		1.22 [1.03–1.44]	0.95 [0.86–1.0]
Esophagus ^a	C15	1.61 [1.18–2.18]	0.96 [0.68–1.3]		3.93 [2.91–5.29]	1.3 [1–1.7]

Oropharynx cancer includes cancers of the tongue, tonsils, and other oropharynx sites.

Other genital cancers include cancers of the vagina, vulva, and penis.

Nonepithelial skin is defined as skin cancers excluding melanoma, Kaposi’s sarcoma, and squamous and basal cell carcinomas.

a Evidence of infection inconclusive (Vadjic et al., 2006).

b Webster AC, Peng A, Kelly PJ. Cancer. In: ANZDATA Registry Report 2012 . 35th Annual Report. Adelaide, South Australia: Australia and New Zealand Dialysis and Transplant Registry; 2012.

c Yanik EL, Clarke CA, Snyder JJ, Pfeiffer RM, Engels EA. Variation in cancer incidence among patients with ESRD during kidney function and nonfunction intervals. J Am Soc Nephrol 2016;27:1495–504.

d Hortlund M, Arroyo Muhr LS, Storm H, Engholm G, Dillner J, Bzhalava D. Cancer risks after solid organ transplantation and after long-term dialysis. Int J Cancer 2017;140:1091–101.

Etiology of the Increased Risk of Cancer in Dialysis Patients

The etiology of cancer risk in dialysis patients includes the presence of chronic infection (especially in the urinary tract), a depressed immune system, previous treatment with immunosuppressive or cytotoxic drugs, nutritional deficiencies, and altered deoxyribonucleic acid (DNA) repair mechanisms. Importantly, cancer is not related to dialysis modality, but rather the uremic state. Uremia is associated with impaired T cell immunity and a state of chronic inflammation, which lead to DNA mutations in proliferating cells and deregulatory release of cytokines implicated in cancer development and progression. CKD also leads to the accumulation of carcinogenic compounds to which dialysis patients are exposed from the environment and possibly in the dialysate. Increasing the frequency of dialysis has been associated with reduced genomic damage and plasma urea concentrations in patients with ESKD. Excess cancer risk may also be due to an interaction of immune dysfunction induced by uremia with established risk factors (ultraviolet [UV] radiation, tobacco, alcohol). Several reports have also demonstrated high levels of cumulative radiation dose in patients with ESKD on dialysis. Although there have been no follow-up studies that have measured cumulative radiation doses and cancer outcomes in patients with ESKD, high exposure (cumulative effective dose >50 mSv) has been reported to increase cancer mortality by 5% in other populations.

In addition to the persistent metabolic changes associated with ESKD, the underlying causative disease, and the development of certain complications of ESKD may also predispose to cancer. The risk of renal cell cancer (RCC) is increased in patients with acquired cystic disease and seems to be related to the total duration of CKD, rather than the duration of dialysis. Other conditions predisposing to cancer include Balkan nephropathy and analgesic nephropathy, both of which are associated with a high risk of developing tumors of the renal pelvis and ureter.

The increased risk of some cancer types is rapidly reversed when immunosuppression is reduced or withdrawn after kidney transplant failure. These cancer types include Kaposi’s sarcoma, non-Hodgkin lymphoma, melanoma, and squamous cell carcinomas of the lip. However, the risk of cancer at other sites remains significantly elevated after iatrogenic immunosuppression is ceased. These cancer types include leukemia, lung cancer, and cancers related to ESKD.

The frequency of viral infections in dialysis patients is poorly documented, but there is no doubt that patients with ESKD have a greater than normal exposure to hepatitis B and hepatitis C viruses, and this probably accounts for the observed excess of liver cancer. Human papillomavirus (HPV) is associated with cancers of the tongue, cervix, vagina, vulva, and penis. HIV is also associated with increased risk of Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and Hodgkin’s lymphoma, lip, and cervical cancers. In both dialysis patients and transplant recipients, the increased risk of lymphoma is thought likely to be due to activation of dormant Epstein-Barr virus (EBV).

Types of Cancer in Dialysis Patients

Renal Tract Malignancy

Risk of renal tract malignancies is particularly high for the dialysis population; risk of renal cancer SIR, 4.03; 95% CI 3.88 to 4 and bladder SIR, 1.57; 95% CI 1.51 to 1.64. Population-specific SIRs are listed in Table 35.1 . The increase in renal tract malignancies during dialysis in the US population is largely driven by localized kidney cancers. In the dialysis population, the risk of developing cancer of the kidney or bladder is relatively (but not absolutely) greater at younger ages, and in women rather than men. The SIR for kidney cancer increases significantly with time on dialysis, whereas the SIR for bladder cancer is progressively decreased. Increased risk for cancers of the urinary tract is associated with increasing duration of maintenance dialysis before first kidney transplant where the adjusted hazard ratio (HR) for urinary tract cancers in recipients that were on dialysis for more than 4.5 years was 2.57 (95% CI 1.33–4.95) compared with those that were on dialysis for less than 1.5 years. However when looking at the differences in absolute terms, this was not significant between groups. There is no excess risk of kidney cancer in patients with ESKD due to autosomal dominant polycystic kidney disease.

Thyroid Cancer

Patients on dialysis are at much higher risk of developing thyroid cancer than the general population or transplant recipients (see Table 35.1 ). CKD has been known to affect thyroid hormone metabolism. The prevalence of subclinical hypothyroidism (21.8%) and nodular thyroid disease (24.1%) are almost three times higher in patients with ESKD than age-, sex-, and weight-matched controls (7.1%). The risk of thyroid cancer is 10.1-fold higher (95% CI 1.12–91.0) in patients with ESKD and secondary hyperparathyroidism. It is thought that a low glomerular filtration rate changes the metabolism of thyroid hormones, although the exact mechanism remains unknown. It may have to do with altered metabolism of iodine, decreased peripheral sensitivity of hormones, or autoimmune thyroiditis. Another possible explanation for the observed increase in risk of thyroid tumors is the repeated imaging of the neck to investigate secondary hyperparathyroidism. Studies assessing cumulative doses of radiation have been too small to prove any association; however, the observation that the frequency of thyroid tumors increases with duration on dialysis supports this hypothesis. Any contribution of overdetection through increases in incidental thyroid imaging in dialysis and transplant patients is difficult to quantify.

Myeloma

Renal disease is common in myeloma and can affect the glomeruli, tubules, and interstitium in isolation or in combination. CKD is noted at presentation in up to half of newly diagnosed myeloma patients but is frequently responsive to the correction of factors contributing to acute injury. The presence and severity of kidney disease correlates with patient survival, and overall prognosis is related to response of the renal disease to therapy. In the past decade there have been major advances in myeloma therapy and management, including autologous stem cell transplant, the use of novel therapeutic agents such as protease inhibitors, and immunomodulatory drugs (bortezomib, lenalidomide, and thalidomide), and the use of the free light chain assay providing greater diagnostic precision, which has significantly improved survival. A recent study predicted 5-year survival of between 12% and 32% dependent on age and improved survival in myeloma patients on peritoneal dialysis compared with hemodialysis (HR 0.7, 95% CI 0.6–0.9).

Dialysis in Patients with a History of Cancer

Rarely, CKD may be a consequence of malignancies directly, in the case of myeloma, or via glomerulopathy, as those arising in lung or colon cancer, possibly as a result of tumor-associated antibodies. Nephrotic syndrome is most often associated with Hodgkin’s disease. Malignant disease of the kidney or ureter can impair kidney function by causing obstruction, and occasionally kidney dysfunction results from a treatment-related nephropathy secondary to toxicity from radiation or drugs.

Cancer Screening and Prevention in Dialysis Patients

There are currently no standard recommendations for cancer screening in the dialysis population. Some authors have suggested that routine cancer screening of patients on long-term dialysis is not cost effective as, unlike the general population, early detection may not lead to improved survival in those with life-limiting ESKD, and treatment effects may not be as certain. Others have argued that selective screening in younger patients and for known cancer types are warranted.

Cost-effectiveness analyses can help put expectations from screening programs into context. Breast cancer screening in women on dialysis has resulted in an absolute reduction in breast cancer mortality of 0.1%, with a net gain in life expectancy of only 1.3 days. The total incremental cost to screen and save one cancer death approximated $403,000 per life-years saved from breast cancer. Similarly, the incremental cost of colorectal cancer screening has been calculated at $122,977 per life-year saved for dialysis patients not listed on the transplant waiting list, and $85,095 for patients on the waiting list, which greatly exceeded the typical thresholds for acceptable cost effectiveness. These costs were largely dependent on the test characteristics of the screening test. In a study where the colorectal cancer screening test had poor sensitivity but reasonable specificity, 69% of cases of advanced cancer would have been missed by immunochemical fecal occult blood test screening alone. Thus surveillance colonoscopy may be a more appropriate approach in patients with ESKD.

For cancers without a screening program in the general population, but which occur more commonly in those on dialysis, there are some situations where targeted screening may be warranted. Screening may be valuable for RCC, where survival is best in young patients with a short duration of dialysis, and when cancer is detected by screening, rather than after causing symptoms. Early diagnosis of RCC by regular imaging of patients with ESKD who are on dialysis would result in an improved outcome.

Management of Cancer in Dialysis Patients

For dialysis patients who have surgical treatment for malignancy, postoperative complications are much higher. Radical nephrectomy may be superior to partial nephrectomy for treatment of localized RCCs, causing 79 fewer deaths per 1000, with no difference in recurrence. Many chemotherapy agents are excreted by the kidney, meaning dosage and scheduling adaptation for those with ESKD. Using available specific drug management recommendations for drug adjustment and avoiding premature elimination of drug during dialysis is paramount. Treatment with radioactive iodine can be undertaken for thyroid cancer in dialysis patients, but dosage adjustment and consideration of bystander exposure is necessary because iodine is cleared mainly by the kidneys or by the dialysis process.

Survival in Dialysis Patients who Develop Cancer

Cancer-specific mortality data in dialysis patients is relatively sparse. In Japan, a nation with a large population of people on long-term dialysis, an analysis of deaths caused by cancer (including renal tract tumors) revealed that the relative risk (RR) of cancer mortality was greatly increased compared with the general population (male RR 2.48; female RR 3.99). A higher cumulative incidence of cancer-specific mortality has been found in patients who initiated dialysis after 2003, compared with previous years. This may be due to improved overall survival in dialysis patients, allowing time for cancer development.

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