ESRD and associated malignancy
A definite association between malignancy and ESRD has been reported.13,14 Stewart et al evaluated 28,855 patients who required renal replacement therapy and reported a fourfold increased incidence of cancer (Figure 1). Immunodeficiency-related cancers were increased from one and a half fold while on dialysis to fivefold after transplantation, and the initiation of anti-rejection medication leads to speculation that this increase is virally mediated.15
Liang et al matched 21,817 ESRD patients in Taiwan to patients from the general population and found the risk of developing cancer was 64% higher in the ESRD patients.16 Lee evaluated 4,582 patients with ESRD and found 106 patients that developed cancer. The most common cancers were in the GI tract (51%), urinary tract (20%) and lung (8%). In this subgroup of patients, 69% of the mortality was due to cancer.17 Mosconi et al evaluated 1,184 Italian patients with ESRD awaiting kidney transplantation and found cancers in 2.2% of patients, most of which were nonmetastatic, arising most commonly from the kidney and thyroid.18
Tickoo and colleagues reported a spectrum of renal neoplasms in kidneys of ESRD patients and stressed the association of acquired cystic disease and associated renal cell carcinoma (ACD-associated RCC) (Figure 2). The tumors often appear as nodules arising in cyst walls, occasionally completely filling the cysts, or can appear as solid tumors distinct from the cysts and can have both solid and papillary architecture.
Multifocality and bilaterality are seen in 50% and 20% of the cases, respectively.19 ESRD patients have a higher prevalence of RCC than the general populations20 and have distinct clinical and pathological features. Neuzillet et al compared the pathologic features of 303 RCC patients with ESRD to 947 sporadic kidney cancer patients and found that the mean age at diagnosis was younger (55 vs. 62), the mean tumor size was smaller (3.7 vs. 7.3 cm), more were asymptomatic (87% vs. 44%), less were high stage (10% vs. 42%), less had nodal metastasis (3% vs. 12%) and less had distant metastasis (2% vs. 15%). After a median follow up of 33 months, 13 ESRD (4.3%) patients had died of RCC vs. 261 (27.6%) from the sporadic tumor population.
The authors concluded that RCC arising in the native kidneys of ESRD patients may be more indolent.21 Hora et al described pathologic characteristics of renal cortical tumors in 19 ESRD kidneys and reported 13 with multiple tumors. Papillary and clear cell tumors alone or in combination were reported.22 Hajj et al reported 89 nephrectomies (including 10 bilateral) from 79 patients with autosomal dominant polycystic disease (ADPKD), 50 of who had ESRD (Figure 3). In 11 of the 89 kidneys, RCC was found including one bilateral and three multifocal tumor. Of these, 58.3% were clear cell and 41.7% tubulopapillary carcinomas. The authors calculated that the prevalence of renal cancer in the combination of ADPKD and ESRD was two to three times more than in ESRD patient’s alone.23
Nouth et al reported a wide spectrum of tumor histology distinct from sporadic RCC in 34 ESRD patients. Pathologic subtypes included ACD-associated RCC, mucinous tubular, spindle cell, and Xp11.2 translocation RCC. In nine of 15 patients with a duration of dialysis less than 10 years, conventional clear cell was the predominant histology whereas ACD-associated RCC was predominant (seven of 12) in those with dialysis of greater than 10 years.24
Suson et al reported 15 post-transplant patients who underwent RN for renal masses in their native kidney. A total of 22 renal units were removed with a total of 18 cancers, 10 of which were P1, resected. There were 11 papillary, four clear cell, and three chromophobe cancers. Only one patient developed metastatic disease.25 These reports, when taken together, describe a propensity for the development of a wide range of RCC in patients with ESRD whose renal tumors may have less metastatic potential than their sporadic counterparts.
CKD and links to cancer
CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73m2, is increasingly viewed as a major public health problem in the U.S. and, since 2003, is considered an independent CV risk factor.26-30 The prevalence of CKD in the general population is 4% but may be as high as 30% in the elderly population.
An estimated 19 million adults in the U.S. have CKD and by the year 2030, two million of these will progress to ESRD and be in need of chronic dialysis or renal transplantation.31 Worldwide epidemics of CV disease, obesity, hypertension and diabetes, all of which can have adverse effects on the kidney, have gained increasing attention but their contribution to the development of CKD has gone relatively unnoticed among clinicians and patients alike. The adverse impact of CKD on CV disease is significant as CKD progresses to ESRD.32
As CKD stages progress there are increased rates of hospitalization, CV events, and death, which occur before overt ESRD requiring dialysis or renal transplantation.33 In addition, as patients drift deeper into the stages of CKD, CV risk factors and requisite medical interventions also increase. The low prevalence of patients with stage 4 or 5 CKD is attributable to a five-year survival rate of only 30%.34
The metabolic consequence of CKD, including anemia, hypocalcemia, hyperphosphatemia, and hyperparathyroidism are particularly marked in patients over 65 years of age.35 This high prevalence of CKD in the aging and elderly is superimposed upon the very patient population most at risk for the development of cancer.
As with ESRD, there are now reports indicating that patients with CKD are at higher risk for the development of cancer in addition to CV disease. Weng et al evaluated 123,717 adults in Taiwan in 1998 and calculated their eGFR. After a median of over seven years, mortality was ascertained by computer linkage to their national death registry. The investigators found a higher overall cancer mortality in CKD patients vs. non-CKD patients. CKD was associated with an adjusted hazard ratio of 1.74, 3.3, and 7.3 for liver, kidney, and urothelial cancers respectively.36
Wong et al evaluated 3,654 patients in Australia aged 49-97 and followed them for a mean 10.1 years. Cancer developed in 711 patients (19.5%). Men with CKD stage 3 were at increased risk for the development of cancer starting at an eGFR of 55 (HR 1.39). For every 10 mL/min decline in eGFR, the risk of cancer rose 29% and was greatest for an eGFR of 40 (HR 3.01) with lung and urinary tract the most likely.37
Cancer patients appear to have a higher rate of CKD than the general population. Launay-Vacher and colleagues evaluated 4,684 patients with cancer, median age 58, and reported that 12% and 20% had an eGFR less than 60 mL/min/ 1.73 m2 by the MDRD study and Cockcroft Gault equations, respectively.38 Canter et al reported the prevalence of baseline CKD in 1,114 patients presenting with solid renal tumors. Twenty-two percent had stage 3 CKD or greater despite 88% having a serum creatinine within normal limits (<1.4 mg/dl).
In a subgroup of 282 patients 70 years or older, 113 (40%) had CKD stage 3.39 These results are similar to those first reported by Memorial Sloan-Kettering Cancer Center investigators, which demonstrated a 26% rate of CKD in 662 patients with small renal tumors and a serum creatinine within normal limits.40