*Łukasz Kozak1, Jacek Janiszewski1, 2, Joanna Woźniak1, 2, Martyna Kamrowska1, Beata Januszko-Giergielewicz3, 4
Colorectal cancer after kidney transplantation – risk factors and the need for prevention
Rak jelita grubego po zabiegu przeszczepienia nerki – czynniki ryzyka i konieczność profilaktyki
1Department of Internal Medicine and Gastroenterology, Independent Public Healthcare Centre, Ministry of the Interior and Administration with Warmia and Mazury Oncology Centre, Olsztyn
2Department of Cardiology and Internal Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn
3Department of General, Liver and Transplant Surgery, Antoni Jurasz University Hospital No. 1 in Bydgoszcz
4Department of Family Medicine and Infectious Diseases, Collegium Medicum, University of Warmia and Mazury in Olsztyn
Przeszczepienie nerki (PN) u pacjentów z przewlekłą chorobą nerek jest uznawane za metodę leczenia nerkozastępczego, która daje im najdłuższe przeżycie oraz najwyższy jego komfort. PN zmniejsza narażenie na wiele powikłań związanych z przewlekłą dializoterapią, umożliwia również pacjentom po transplantacji tego narządu pełne funkcjonowanie w środowisku rodzinnym oraz społecznym. Jak każda forma leczenia posiada ona jednak swoje ograniczenia. Spowodowane są one przede wszystkim koniecznością stosowania przewlekłego leczenia immunosupresyjnego. Udowodniono, że przewlekła immunosupresja zwiększa ryzyko występowanie nowotworów. Najczęściej występującymi nowotworami mającymi związek z immunosupresją są nowotwory skóry. Również ryzyko rozwoju raków narządów litych jest kilkakrotnie wyższe po PN w porównaniu z populacją ogólną. Choroby nowotworowe są jedną z głównych przyczyn zgonów chorych po PN. Wynika to z podstępnego i agresywnego ich przebiegu w tej populacji pacjentów oraz częstej konieczności modyfikowania stosowanej terapii onkologicznej. W przedstawionej pracy, na podstawie analizy dostępnych danych z piśmiennictwa oraz doświadczeń własnych, autorzy dyskutują fakt zwiększonej częstości występowania raka jelita grubego (RJG) u chorych po PN, odmienności jego przebiegu oraz potencjalnych możliwości jego profilaktyki w tej szczególnej grupie chorych. W oparciu o tę analizę autorzy postulują również konieczność wprowadzenia ścisłych, ujednoliconych dla wszystkich ośrodków transplantacyjnych zaleceń, dotyczących nadzoru onkologicznego w kierunku wczesnej wykrywalności RJG u pacjentów po PN.
Kidney transplantation (KT) in patients with chronic kidney disease is considered a method of renal replacement therapy offering the longest and most comfortable survival possible. Kidney transplantation reduces the risk of multiple complications associated with chronic dialysis, as well as allows patients after transplantation of this organ for full participation in family and social life. However, like any other treatment modality, kidney transplantation has its limitations. These are primarily associated with the need for chronic immunosuppressive therapy. It was shown that chronic immunosuppression increases the risk of cancer. Skin cancers are the most common immunosuppression-related neoplasms. Also, the risk of solid organ cancers is several times higher after kidney transplantation compared to the general population. Cancer is one of the leading causes of mortality in kidney graft recipients. This is due to its insidious and aggressive course in this patient population and the frequent need to modify anticancer therapy. In this paper, we discuss the increased incidence of colorectal cancer (CRC) in patients after kidney transplantation, differences in the course of the disease, as well as its potential prevention, based on the available literature and our own experience. Based on our analysis, we postulate the need for strict recommendations unified for all transplantation centres, regarding oncological surveillance for early detection of colorectal cancer in patients after kidney transplantation.
The shortage of organs for transplantation is a widely known problem of modern transplantation medicine, which is broadly discussed in medical societies. Combating the main causes of shorter survival in organ transplant recipients, such as cardiovascular complications and more aggressive development of malignancies compared to the general population, is no less challenging.
The kidney is the most commonly transplanted vascularised organ both in Poland and worldwide. A total of 1,473 transplantations from deceased donors, including 907 kidneys, were performed in Poland in 2019. A total of 73 organs, including 52 kidneys, were transplanted from live donors. These statistics have not changed significantly for several years, and the expected progress has not been made in this respect. A total of 1,947 patients awaited organ transplantation in Poland in 2019, including 50% of patients on the waiting list for the kidney (1). The above data illustrate the size of the described patient population. These patients require particularly increased oncological vigilance and special standards for cancer prevention.
As mentioned above, cancer is one of the leading causes of mortality in patients after kidney transplantation (KT), who are at an increased risk of malignancy compared to the general population (2, 3).
Colorectal cancer (CRC) is the third most common malignancy in men and the second most common malignancy in women. It accounts for 8% of cancer-related deaths, which makes it the fourth leading cause of cancer-related mortality globally. CRC is responsible for about 600,000 deaths annually (4). Most cases of CRC are sporadic, with only about 5-10% of cases due to genetic predisposition (4).
CRC is 2-3 times more common in patients after KT compared to the general population (5); it shows more rapid and aggressive growth pattern, the affected recipients are younger at diagnosis, and they have worse treatment outcomes (6). It should be emphasised that a kidney transplanted from a deceased and a living donor functions for an average of 7-10 and about 15 years, respectively (7). Therefore, there is a high probability of neoplastic process initiation in predisposed patients during the period of good graft function, which is often observed in everyday practice.
Risk factors for colorectal cancer
In 2013, Johnson et al. analysed the available literature and identified the following risk factors for CRC: overweight and obesity, lack of physical activity, smoking tobacco, diabetes, inflammatory bowel diseases, excess consumption of alcohol, pelvic radiotherapy, and acromegaly. The important role of genetic factors, such as family history of CRC, Lynch syndrome, type X CRC, familial adenomatous polyposis, Peutz-Jeghers syndrome and MYH-associated polyposis, was also emphasised (8).
CRC risk factors postulated by the National Cancer Registry are shown in table 1 (4).
Tab. 1. Risk factors for colorectal cancer according to the National Cancer Registry (4)
|Age||Increased risk after the age of 50 years|
|Inflammatory bowel diseases||Ulcerative colitis – 20-fold increase in the risk, Crohn’s disease – 3-fold increase in the risk|
|Metabolic syndrome||Hypertension, obesity, diabetes, hypertriglyceridaemia, low HDL cholesterol – increased risk, mainly in men|
|Smoking tobacco||1/5 of CRCs are associated with tobacco smoking in the USA|
|Lifestyle||Poor physical activity|
|Race||Higher risk among African Americans and Ashkenazi Jews|
|Geographical factors||More common in Europe, North America, Australia and Japan than in Africa or Asia|
|Positive history of adenomas or CRC|| |
|Genetic factors||Familial adenomatous polyposis (FAP) is associated with a 100% lifetime risk of developing CRC|
Hereditary non-polyposis colorectal cancer (HNPCC) – 70-80% risk of CRC
|Diet||Low-fibre, high-fat, high-calorie diet low in calcium, alcohol abuse|
|Previous history of abdominal radiation therapy|| |
| Prior cholecystectomy|| |
|Ureterosigmoidostomy||500-fold increased risk|
|Family history of CRC in the absence of signs of classical genetic predisposition syndrome || |
It seems that diet is the most important environmental factor involved in the aetiology of CRC. The impact of diet high in red meat on the increased risk of CRC has been documented in numerous studies (9). This causal relationship may be either direct or indirect as a meat-rich diet may be deficient in other components, such as fibre and fruit/vegetable polyphenols (10). Thermal processing of meat itself can also contribute to its increased carcinogenic potential. When meats are cooked at higher temperatures, mutagenic and carcinogenic heterocyclic amines are formed as a result of interaction between muscle creatinine and amino acids (11), as well as N-nitroso compounds are formed (12). The heme contained in meat may act as a nitrosating agent, promoting formation of N-nitroso compounds. Since red meats have a higher content of heme than white meats, high consumption of red meat (beef, pork or lamb) may increase the risk of CRC (13, 14). A relationship was demonstrated between heme iron and colonic polyps, adenomas and CRC (15-18). Diet low in selenium and plant fibres also plays an important role. It has negative effects on the intestinal bacterial flora, induces synthesis of carcinogens and slows their passage through the large intestine (19).
Type 2 diabetes is known to be associated with an increased risk of CRC. Larsson et al. demonstrated a strong correlation between type 2 diabetes and an increased incidence of CRC in their 2005 meta-analysis (20). Based on an analysis of 15 studies, the authors concluded that the risk of CRC is increased in T2D (20-22).
This hypothesis was confirmed in 2015 by Díaz-Algorri et al., who assessed a group of 451 patients. Based on the collected evidence they found that type 2 diabetes is an important risk factor for colorectal neoplasia, especially in women (23, 24).
Insulin and insulin-like growth factor (IGF-1) are known to play an important role in human metabolism, but they are also responsible for regulating cellular growth and proliferation. In addition to its role in glucose metabolism, insulin also stimulates colon epithelial growth. CRC epithelial cells have been shown to have an increased density of insulin receptors compared to normal colonic epithelium (22). It should be emphasised that the pro-proliferative effects of insulin have been shown only at its plasma levels above physiological norms (25).
Colonic and CRC epithelial cells express IGF-1 receptors. Activation of IGF-1 leads to apoptosis inhibition and cell cycle progression (26). Insulin and IGF-1 have no direct mutagenic effect. The pattern of colonic transformations follows the adenocarcinoma-cancer sequence in patients with type 2 diabetes, while insulin and IGF-1 can only accelerate this process (22).
As already mentioned above, the risk of CRC is also increased in obese individuals (27). The risk of colon cancer is significantly increased in obese men and women, with stronger carcinogenesis in obese men than women (28). It was also found that individuals with abdominal obesity have an increased risk of developing adenoma compared to those non-obese (29).
Also, it was clearly demonstrated that tobacco smokers are at an increased risk of death from CRC (30, 31). This risk is proportional to the number of cigarettes smoked per day (pack years) (32). Smoking is also associated with an increased risk of developing colorectal polyps (33).
Risk factors and the course of colorectal cancer after kidney transplantation
In addition to the above mentioned risk factors characteristic for the general population, patients after KT are exposed to additional risk factors specific for this group. Therefore, these patients are exposed both to traditional risk factors for CRC, which are proven in the literature, and risk factors resulting from chronic kidney disease (CKD) and immunosuppressive therapy. Patients with CKD are at an increased risk of cancer compared to the general population due to immune dysfunction, impaired DNA repair, higher levels of reactive oxygen species, carcinogenic effects of heterocyclic amines and nitrosodimethylamines, increased levels of parathyroid hormone, reduced levels of 1,25-dihydroxycholecalciferol, and increased inflammatory markers. Pharmacotherapy (previous immunosuppressive treatment, excess use of analgesics, the use of diuretics) and previous dialysis therapy, which is often associated with the use of iron and/or erythropoietin therapy, also play an important role in carcinogenesis. The duration of dialysis is also important – the risk of cancer increases by 10-20% per year for dialysis duration over 2-3 years (34, 35).
In the case of KT, the possible donor/recipient cancer transmission (0.02-0.2% of all transplantation) is an important factor contributing to cancer development in the latter (34, 36). A relatively high risk of donor-recipient transmission has been observed for renal cell carcinoma, malignant melanoma, lymphoma, lung cancer, breast cancer, choriocarcinoma, and CRC in the donor (34).
Immunosuppressants, their type and duration of their use have a significant impact on carcinogenesis. This results indirectly from the immune response as well as from the direct pro-oncogenic effects of these agents (37, 38). It was demonstrated that the risk of cancer increases with an increasing total intensity of immunosuppressive therapy (39).
Usually triple immunosuppressive regimens are used after KT due to the high immunogenicity of this organ; therefore, due to the intensity of immunosuppression, the risk of CRC after KT is higher compared to other organs, such as the liver, where mono- or dual-immunosuppression is sufficient to maintain good function of transplanted liver (40-42).
The risk of death significantly increases 10 years after transplantation. Compared to the general population, CRC is more common in younger patients after KT (58 vs 70 years) and is associated with worse prognosis (5-year survival 43.5 vs 62.3%) (43, 44). The characteristic of CRC after KT is presented in table 2.
Tab. 2. Risk factors for colorectal cancer after kidney transplantation (34, 37, 39)
|Time since KT||Significantly increased risk 10 years after KT|
|Underlying kidney disease and its treatment prior to KT||Increased risk is associated with previous immunosuppressive therapy, steroid therapy and the length of dialysis therapy.|
|Age||Disease onset at a younger age than in the general population|
|Aggressive course of the disease||More rapid progression of untreated CRC than in the general population|
|Type of immunosuppressive therapy used after KT||The risk varies, depending on agents used and immunosuppression regimen (dual, triple)|
KT – kidney transplantation; CRC – colorectal cancer
Most CRCs histologically arise from benign lesions, i.e. adenomatous polyps. Polyps and early-stage cancer are usually asymptomatic (45) until advanced stage of the disease. This is particularly dangerous in patients after KT due to therapeutic difficulties in advanced stages of the disease, which result from the possible dysfunction of the transplanted kidney and the resulting limitations and/or contraindications for chemotherapy.
Mayo Clinic researchers published an analysis of 115 patients after solid organ transplantation, of whom 63 met the inclusion criteria (the excluded patients had cancer diagnosed prior to transplantation) and developed CRC after transplantation (46). The study group included 44% of patients after kidney and 35% after liver transplantation. Mean time elapsed between transplantation and CRC diagnosis was 59 months; with stage 4 CRC in 15 patients and stage 3 CRC in 13 patients. Mean survival time was 30.8 months. The estimated 5-, 10- and 15-year survival rates were 42.5, 17.9 and 7.5%, respectively. None of patients with stage 4 CRC survived 5 years. The estimated 5-year survival rates for patients with stage 1, 2 and 3 CRC were 77, 50, and 42%, respectively (46).
In 2016, a team of Polish researchers from the Medical University of Gdańsk published a study describing their attempt to investigate a group of 950 patients under the care of a nephrological clinic (47). Of this group, only 180 patients completed a questionnaire on the alarming symptoms of CRC, and 100 of these patients had faecal occult blood test (FOBT) performed. Based on preliminary results, 45 patients were qualified for endoscopy. In this group, colonic diverticulitis was diagnosed in 18, colonic polyps in 14, inflammatory bowel disease in 7, and CRC in 3 patients (47).
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