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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
Kidney cancer-associated nephropathology The extent to which ESRD- or CKDassociated nephropathological changes are simply associated with RCC or cause RCC is unknown. In patients with ESRD, numerous renal cysts develop and persistently grow in native kidneys even after
transplantation. Goh et al reported 10 asymptomatic transplant recipients who developed RCC in native kidneys at a median of 5.8 years, while their grafts were functioning at a greater than 90% rate. The patients at greatest risk for developing RCC were those with preexisting renal cysts and those on dialysis the longest.41 In patients without ESRD/ CKD and renal cancer, many nephropathological changes are observed. Bijol et al examined the nontumor-bearing normal appearing kidney in 110 nephrectomy specimens resected for RCC. Extensive and unsuspected underlying renal disease (including vascular sclerosis, diabetic nephropathy, glomerular hypertrophy, mesangial expansion, and diffuse glomerulosclerosis) was reported. Only 10% of patients had completely normal renal tissue adjacent to the tumor.42 Henriksen and colleagues confirmed a wide range of kidney abnormalities in the non-neoplastic kidney, including mesangial sclerosis or hypercellularity, segmental sclerosis, crescent formation, glomerulitis, and glomerular basement membrane disease.43 Pathologists are now being urged to routinely report these findings in tumor nephrectomy specimens.44 The precise mechanism by which the uremic state, dialysis, and transplantation can cause malignant transformation in the kidney is unknown. Cancer-induced paraneoplastic nephropathy, exposure to toxins, viral-mediated carcinogenesis, immune inhibition, and circulating toxins have all been implicated.45 Retention of uremic toxins, such as p-cresol, could also promote malignant transformation by their inhibitory effect on the immune system and transendothelial leukocyte migration.46,47 In the last decade, the surgical management of renal tumors has shifted from the historical RN for all tumors of all sizes48,49 to PN whenever possible. Unlike the carefully screened kidney transplantation donors, RCC patients were older, often had common medical comorbidities such as hypertension, diabetes and vascular disease,50-52 and experienced an agerelated decline in baseline GFR. 53 In addition, the oncologic results of RN and PN were equivalent for small renal masses but RN patients experienced rising creatinine, albuminuria, and a greater likelihood of new-onset CKD as determined by eGFR.40,54,55 Other studies indicated that the RN
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patients had worse overall survival and a greater likelihood of a CV event.56-58 A recent pooled analysis of 51 studies involving 31,728 patients from the world’s literature was published by Kim and colleagues. The authors reported that PN was associated with a 19% risk reduction in all-cause mortality, a 29% risk reduction in cancer-specific mortality, and a 61% risk reduction in severe CKD. Despite these findings, the authors pointed out that the data obtained were observational and subject to selection biases and statistical heterogeneity.59 Similar results were reported in patients undergoing laparoscopic RN and PN.60 The effect of these reports has made urologists increasingly aware that pre-existing CKD can be significantly worsened by the liberal use of RN for the treatment of the small renal mass.61 Short-term endpoints, including length of hospital stay, analgesic requirements, and cosmetic elements, viewed by many as the reason to elect laparoscopic RN over the more challenging PN, must now be tempered by these new concerns regarding CKD and overall survival. The most recent American Urological Association guidelines for the management of the small renal tumor emphasize these points and strongly support the use of PN whenever technically feasible.62 Despite this information, evidence of overutilization of RN exists when databases such as the National Inpatient Sample.63 SEER,64 and SEER linked to Medicare57,58 are analyzed with an approximately 70% RN rate even for tumors of 4 cm or less. For uncertain reasons, women and elderly patients are more likely to be treated with RN.65
Conclusions Renal insufficiency, ESRD, and CKD are associated with the development of RCC. Unlike healthy kidney donors used for transplantation, kidney tumor patients are older, have common medical comorbidities that can affect the kidneys and CV system, and have a higher rate of baseline CKD (up to 40%) than the general patient population. In the nonneoplastic kidney at the time of nephrectomy, extensive nephropathologic findings are observed in the vast majority of patients with RCC. It is unknown if these changes somehow induce renal neoplasia or are simply a result of medical comorbidities that are prevalent in the
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kidney tumor patients. The precise mechanism by which the uremic state causes malignant transformation is unknown but it is speculated that uremic toxins, viral mediators, and immune inhibition could play a role. For surgeons operating on small renal tumors, it is now clear that PN provides equivalent oncologic results to RN while at the same time maximally preserving renal function and preventing or delaying the onset of CKD and its late CV morbidity and mortality. Despite a decade of clinical evidence in support of PN, RN remains overutilized in the United States and abroad. Formal support for PN in the management of small renal masses has been made by major urological surgical organizations. A working knowledge of the relationship of CKD/ ESRD and RCC is now essential for all urological oncologists. ■
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