Saudi Journal of Kidney Diseases and Transplantation

: 2003  |  Volume : 14  |  Issue : 1  |  Page : 5--14

Malignancy and Chronic Renal Failure

Ramon Peces 
 Servicio de Nefrologia, Hospital Universitario La Paz, Madrid, Spain

Correspondence Address:
Ramon Peces
Servicio de Nefrología, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid


Increased incidence of cancer at various sites is observed in patients with end-stage renal disease (ESRD). Certain malignant diseases, such as lymphomas and carcinomas of the kidney, prostate, liver and uterus, show an enhanced prevalence compared with the general population. In particular, renal cell carcinoma (RCC) shows an excess incidence in ESRD patients. A multitude of factors, directly or indirectly associated with the renal disease and the treatment regimens, may contribute to the increased tumor formation in these patients. Patients undergoing renal replacement therapy (RRT) are prone to develop acquired cystic kidney disease (ACKD), which may subsequently lead to the development of RCC. In pre-dialysis patients with coexistent renal disease, as in dialysis and transplant patients, the presence of ACKD may predispose to RCC. Previous use of cytotoxic drugs (eg, cyclophosphamide) or a history of analgesic abuse, are additional risk factors for malignancy. Malignancy following renal transplantation is an important medical problem during the follow-up. The most common malignancies are lymphoproliferative disorders (early after transplantation) and skin carcinomas (late after transplantation). Another important confounder for risk of malignancy after renal transplantation is the type of immunosuppression. The type of malignancy is different in various countries and dependent on genetic and environmental factors. Finally, previous cancer treatment in a uremic patient on the transplant waiting list is of great importance in relation to waiting time and post-malignancy screening.

How to cite this article:
Peces R. Malignancy and Chronic Renal Failure.Saudi J Kidney Dis Transpl 2003;14:5-14

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Peces R. Malignancy and Chronic Renal Failure. Saudi J Kidney Dis Transpl [serial online] 2003 [cited 2021 Jan 24 ];14:5-14
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 Frequency of Malignancy in Chronic Renal Failure (CRF) Patients

The risk of cancer is increased during dialysis compared with the background population, as documented by the combined data of three different registries. [1] In younger patients on dialysis, statistics have indicated a higher frequency of cancers of the kidney, bladder, tongue, liver, lower genital tract in women, external genitalia in men, and thyroid as well as lymphomas and multiple myeloma. The high frequency of kidney cancers is due to the fact that acquired cystic kidney disease (ACKD) of the recipient's own kidney is a premalignant condition. The prevalence of renal cell carcinoma (RCC) in hemo­dialysis and renal transplant patients is approximately 40 to 100 times greater than that in the general population. [2],[3],[4] On the other hand, we have reported a 2% incidence of end-stage renal disease (ESRD) from uni­lateral RCC and associated pathology in the contralateral kidney. [5] The overall incidence of malignancy after transplantation is three to five times higher than in the general population. [6],[7],[8],[9] Such excess frequency is not found for all malignancies but only for some, particularly lymphoproliferative disorders and squamous cell carcinoma (lip, cervix, vulva, skin). [10] The cumulative prevalence of malignancy increases with the duration of follow-up. The duration and intensity of immunosuppression are important risk factors for the development of post-transplant malig­nancies. The particular propensity of the graft recipient to develop malignancy may explain that multiple tumors are more frequent than in the background population. [10],[11] Another argument along the same line is that the age of onset of malignancy tends to be younger in graft recipients compared with the general population.

Although the pathogenetic mechanisms responsible for the increased cancer incidence have not been fully elucidated yet, a multitude of factors directly or indirectly associated with the renal disease and the treatment regimens may contribute to the increased tumor formation in these patients.

 Renal Disease as Predisposing Factor of Cancers of the Kidney and Urinary Tract

ACKD, which is observed in 7-22% of the predialysis patients and in the course of hemodialysis or peritoneal dialysis in up to 90% of the patients, is frequently associated with RCC. To date, the pathogenesis of ACKD and the associated RCC remains unsolved. Several factors are considered to contribute to the development of ACKD and RCC in CRF patients: ischemia, obstruction of renal tubules due to oxa­late deposits, uremic metabolism, dialysis related substances, genetic changes and growth factors. The lining of the epithelium of these cysts usually manifests varying degrees of proliferation, subsequently leading to dysplasia, adenoma, and carcinoma. The factors responsible for the proliferative changes in renal tubular epithelium are poorly understood. It has been suggested that severely altered microenvironment of the cells in the end-stage kidney may cause the release of certain growth factors. Such factors, acting as ligands for surface receptors on surviving renal cells, could enhance prolix­feration in the end-stage kidney. [12],[13],[14]

In von Hippel-Lindau (VHL) syndrome, coexistence of multiple, bilateral cysts of the kidney with RCC are a typical finding. [15],[16],[17] In tuberous sclerosis, the most frequently encoun­tered renal lesion is the angiomyo-lipoma, but patients with this disease have an increased risk of the development of RCC. [18]

In a high proportion of hemodialysis patients, long-term analgesic abuse is the cause of renal failure, which may be associated with urothelial carcinomas as well as RCC in particular, after renal transplantation. [19] It is of clinical importance that the excess risk of developing uroepithelial carcinoma after phenacetin abuse persists for decades after cessation of phenacetin. Balkan endemic nephropathy has been associated with increa-sed formation of urinary tract tumors. [20] Chinese herbs neph-ropathy has also been associated with increased formation of urothelial carcinoma. [21]

 Diabetes and Hypertension

Recent findings suggest that nephrosclerosis and intratubular epithelial dysplasia asso­ciated with RCC might represent unrecog­nized precursor lesions along the spectrum ranging from dysplasia to frank carci­noma. [22],[23] In hypertension, a variety of angiogenic and other growth factors, the levels of which are increased in persons with hypertensive disease, may be involved in renal carcinogenesis. A similar mechanism may be involved in the development of RCC among diabetic patients. [24] Subtle changes in renal function that precede the development of overt systemic or intraglomerular hyper­tension may render the kidney susceptible to carcinogens and tumor growth. [25] The preva­lence of these tumors is correlated with the presence and severity of nephrosclerosis and it has been suggested that tumor development is promoted by renal scarring. The severe nephrosclerosis of CRF dissects the nephron into unattached tubular and cystic elements that show both atrophic and hyperplastic changes. Hyperplasia seems to represent attempts at regeneration promoted by reno­tropic substances that have the attributes of growth factors. [13] Thus, it has been demon­strated that patients with mild CRF may develop ACKD in various renal diseases. [26] Renal cyst development may be a manifesta­tion of tubulo-interstitial damage and a part of sclerosing kidneys in addition to glomerular sclerosis and interstitial fibrosis.

 Role of Tobacco

Smoking is a major oxidative stress in addition to being a source of mutagens. In particular, for cancer of the kidney and the urinary tract, the pathogenetic role of smoking has been demonstrated. [19],[27],[28] Furthermore, in some virus-induced malignancies such as cancer of cervix uteri, nicotine has been assumed as a cocarcinogen. In ESRD, the consequences of smoking may be aggra­vated by the accumulation of nicotine. On the other hand, the risk for developing bronchial carcinoma in a smoking renal allograft recipient is higher. [28],[29]

 Renal Malformations

Familial and genetic factors are well documented in VHL disease, in hereditary papillary RCC, in the tuberous sclerosis complex and in familial RCC. [15],[16],[17],[18] In addition, some patients have renal malformations and could have an increased risk of developing RCC. [30]

 Role of Genetic Factors

Currently, there is great interest in the genetic predisposition to malignancy. Specific RCC variants have distinctive chromosome alterations and several genes have been implicated in the development of RCC. Loss of material from the 3p chromosome characterizes conventional RCC and the deletion of the VHL suppressor gene plays an important role in the genesis of this RCC variant. In contrast, numerical changes with trisomy of chromosomes 7 and 17 and loss of the sex chromosome are typical changes in papillary tumors, whereas papillary RCC has additional trisomies. [3],[31]

Some selected information on this point is available for graft recipients. In renal allo­graft recipients, the risk of a first malig­nancy is definitely higher, but according to one study, patients with a history of invasive carcinoma before transplantation had a higher risk for developing a second invasive carcinoma de novo. [28] Some rare primary renal diseases (e.g., VHL disease) have an intrinsically higher risk for developing RCC with a more aggressive clinical course. When these patients receive a renal graft, the frequency of RCC is increased further. [15] The carcinogenic risk is increased in Wiskott-Aldrich syndrome and Drash syndrome, both rare syndromes. In these conditions, malignancies (lymphoma, Wilms' tumor) have been observed after renal transplantation. [32],[33] A further observation is compatible with a genetic predisposition. Patients with tumors after renal trans­plantation often have more than one tumor type. Thus, patients with three different tumors have been reported. [34]

 Geographic Differences

Recently, a large international collabo­rative study on cancer in patients on dialysis for ESRD was published. 1 Prevalence of cancer on dialysis was highest in Australia/ New Zealand, followed by United States and Europe. In all three cohorts, the greatest incidence of cancer was observed in younger patients ( 65 years). There is evidence that the risk of cancer is already enhanced in pre-ESRD. The high incidence of malignancies within the first year of dialysis underlines the importance of the pre-dialysis period for the development of cancer, because most cancer types have latency periods of several years.

The observation of geographic differences in the pattern of malignancies after renal allograft transplantation provides an illus­trative lesson on potential risk factors. In Japan, the most frequent types are digestive organs (50%) (liver, stomach, colon, rectum) whereas the incidence of skin cancer and lymphoma is low. [35] In the United Kingdom, the most frequent malignancies are lym­phoma, renal cell carcinoma, carcinoma of the digestive organs, and bronchiocarci­noma. [36] In Saudi Arabia, the most frequently reported malignancies are Kaposi's sarcoma, lymphoma (particularly in children), skin malignancy with melanoma being more frequent in children than in adults, and anogenital cancers. [37] In Australia, the risk of skin cancers is overwhelming, particularly spinocellular carcinoma, which is seen in 70% of long-term renal allograft recipients in the subtropical state of Queensland. [38] In South East Asia, where hepatitis B and C infection is endemic, a high incidence of liver cancer is observed after renal trans­plantation in Taiwan. [39],[40],[41] There are diffe­rences between the United States and Europe. The higher frequency of lympho­proliferative disease and lymphoma in the United States has been ascribed to the more frequent use of polyclonal and monoclonal antibodies and generally heavier immunosup­pression. [42]

Although part of the geographic variations in incidence could be due to differences in diagnostic intensity and autopsy rates, the importance of environmental factors in carcinogenesis are likely to be substantial.

 Impaired DNA Repair after Long-term Renal Replacement Therapy

Cellular ability to repair DNA damage is a major defense mechanism against cancer. Several convincing data show significant changes in the DNA repair both before start of dialysis [43] and after long-term RRT. [44] In line with these studies, an increased damage in lymphocytes of patients before and after long-term hemodialysis therapy has been demonstrated by assessing the number of micronuclei, which are cytoplasmic DNA-containing structures. [45] Interestingly, even in rats with moderate renal insufficiency, DNA damage of lymphocytes could be demonstrated. In addition, cyclosporin is responsible of impaired DNA repair in kidney transplant recipients. [46]

 Role of Impaired Function of the Immune System

Both cellular and humoral immune responses are frequently impaired in ESRD. Uremic patients show a decreased response to immunization, prolonged graft survival, reduced circulating B - and T-lymphocytes, reduced helper to suppressor T-cell ratio and delayed cutaneous hypersensitivity. [47],[48],[49],[50] In addition to the underlying renal disease, the kind of renal replacement therapy may also modulate the function of the immune system. Part of the ESRD patients have immuno­suppressive medication in their medical history, most of them in the course of glome­rulonephritis or prior unsuccessful renal transplantation. Immunosuppressive therapy with azathioprine, methotrexate, cyclophos­phamide and particularly cyclosporine may give rise to enhanced prevalence of carcinomas of the skin, lips, uterus, bladder and liver as well as lymphomas and sarcomas. [51],[52],[53],[53]

The high frequency of malignancy in the graft recipient is due to a defect of immuno­surveillance. Although immunosuppression is a necessary condition, it presumably is not sufficient per se. One additional factor may be infections with potentially oncogenic viruses, which are responsible mainly for early lymphatic tumors. The role of viruses in the genesis of tumors that occur later in the post­transplantation course is less clear, but the role of papillomavirus has been establi­shed. [54] The role of human papilloma-virus (HPV) has been well established for spino­cellular carcinoma of the skin and for cervical carcinoma. [55] With the introduction of new immunosuppressive regimens, the frequency of cancers after renal transplan-tation has increased. There is no doubt that in patients on triple-drug therapy including cyclosporine, azathioprine, and corticosteroids, malignancies are more frequent. [56] The risk of malignancy in heavily immunosuppressed patients is due primarily to the development of lym­phomas, which are observed most frequently in patients receiving polyclonal or monoclonal antibodies for induction or rescue therapy. [57] A high risk of malignancy was found in patients receiving the combination of monoclonal antibodies, tacrolimus, and mycophenolate mofetil. [58]

 Role of Oncogenic Virus

Susceptibility to oncogenic viruses in the dialysis patient has been linked to uremic immunodeficiency. In particular, one report indicates the excessive prevalence of HPV DNA in maintenance hemodialysis patients. [59] Some types of enhanced cancer risk were linked to infections with oncogenic viruses such as carcinoma of the tongue (HPV-16), cervix uteri (HPV-16 and HPV-18), and liver (hepatitis B and C virus infection). [1] In Japan, increased adult T-cell leukemias are also described in RRT patients due to an activation of oncogenic human T-cell leukemia virus type 1. [60]

In renal transplant recipients, infections with potentially oncogenic viruses are responsible mainly for early lymphatic tumors. Some types of enhanced cancer risk are linked to infections with oncogenic viruses such as lymphoma (Epstein-Barr virus), Kaposi's sarcoma (HHV8), carcinoma of the cervix, penis, and vulva (HPV). [61]

 Is the Enhanced Cancer Incidence of the RRT Patient a Reflection of a Better Surveillance?

RRT is an exceptional opportunity for early detection of malignancies. This is particularly true for cancer of the kidney, but also of the thyroid, which is frequently investigated in the diagnostic program of hyperparathyroidism. Therefore, excess ele­vation of cancer incidence may be, at least in part, a consequence of better surveillance.

Thus, increasing detection of presymptomatic tumors by imaging procedures may be contributing to the rapidly increasing incidence of RCC. [5],[62],[63] In our study, [64] whereas RCC in the majority of patients without RRT, was discovered incidentally during the work-up of renal disease, in dialysis and transplant most tumors were discovered through ultrasound screening for patients with ACKD. Many cases of RCC have very low cell kinetics. Paradoxically, a large proportion of the neoplasms manifested when they were > 5 cm in greatest diameter. This finding indicates that the tumors might exist for prolonged periods before clinical expression. Since the majority of the patients were asymptomatic, ultrasonography or computed tomography (CT) may be a useful tool in the review of CRF and renal transplant patients and allow early diagnosis and surgical treatment of early stage, low­grade tumors and therefore, may have better survival. [3],[65],[66]

 Screening of the RRT Patient for Malignancy

There are no established guidelines for cancer screening in patients with ESRD. Regular screening is advisable when a patient has been considered for renal transplan­tation and particularly after renal transplan­tation has been performed. In high-risk patients, more frequent screening is indicated. Regular screening of the skin is rewarding because squamous cell carcinoma of the skin usually is preceded by precancerous states. In women, regular gynecologic examinations, including Papanicolaou smears, and trans­vaginal ultrasonography are mandatory to exclude vulvar, perineal, and uterine malig­nancies. In renal transplant patients, ultra­sonographic examination (in case of doubt, CT scan) of the recipient's own kidneys is mandatory at least at yearly intervals. [62],[63] Urologic examination is indicated in patients with a history of analgesic nephro­pathy, patients who had received cyclophos­phamide for the treatment of their primary disease and patients who have been treated with azathioprine for more than 10 years. After renal transplan-tation, screening for colonic carcinoma is indicated. The high­risk group of patients with a history of ureterosigmoidostomy should undergo colonoscopy at least 10 years after renal transplantation because of the risk of late colonic carcinoma. The value of tumor markers in screening for malignancy is controversial. [61]

Today, transplanted tumors have become rare because of increased awareness of the problem. [67]

 Management of the RRT Patient with Malignancy

In patients for whom transplantation is considered, occasionally the issue arises whether a history of malignancy is a contra­indication to renal transplantation. There is consensus that a 2-year waiting period should be interposed between treatment of the cancer and transplantation. In incidentally discovered RCC, in situ carcinoma, low­grade bladder cancers, and basal cell carcinoma of the skin, a waiting period is not required. A waiting period of more than 2 years is advisable in patients with a history of malignant melanoma, breast cancer, and colorectal carcinoma. There is no absolutely safe threshold, however, and late recurrence of breast cancer has been observed in graft recipients. [68] In the patient with malignancy arising de novo after renal transplantation, the issue must be addressed whether reduction or cessation of immunosuppression would permit rejection of the malignancy by the immune system of the allograft recipient. Reduction or cessation of immunosup­pression has proved to be successful in patients with post-transplant non-Hodgkin lymphoma and Kaposi's sarcoma. A particular case is the patient with Kaposi's sarcoma. Reduction of immunosuppression is followed by complete remission in 30% of patients. Localized lesions may be treated surgically and by local radiation. Widespread Kaposi's sarcoma should be treated with chemotherapy, but general guidelines are not available yet. [61] It is recommended to treat solid tumors similarly as in nonimmunosuppressed patients.


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