Kidney Failure with Urinary Tract Cancers

• ESKD
• kidney cancer
• transplantation
• mortality risk
• urologic neoplasms
• renal insufficiency

There has been a recent surge in interest in the interplay between cancer and kidney disease. Both conditions are associated with significant morbidity and mortality; cancer increases risk of kidney disease, and patients with kidney disease have increased risk of cancer (1).

Novel therapies, including immunotherapy, targeted therapies, and precision medicine, have resulted in improved survival for several malignancies (1). The prevalence of CKD in patients with cancer varies depending on the malignancy, stage, and treatment but generally seems to be increasing (2,3). Preexisting CKD and CKD risk factors are high among those with renal cell carcinoma (RCC) (4). AKI, a CKD risk factor, has been increasing among those with cancer as well, with the prevalence rising from 2.0% to 10.4% over a decade in one study (5). Conversely, patients with ESKD have increased risk of cancer and mortality due to cancer (6,7). For CKD, cancer risk seems to be increased with selective cancers, such as urothelial cancers (8). Cancer mortality worsens as CKD progresses. The reasons for this are likely multifold, including limited access to transplantation and avoidance of indicated tests (including contrast-enhanced imaging), as well as use of chemotherapies with uncertain kinetics or decreased efficacy due to kidney disease (1).

As patients with cancer and CKD approach the need for KRT, there are many uncertainties in their care. Dose and frequency of most chemotherapeutic agents have not been studied in the setting of dialysis, including timing regarding dialysis schedule. In those who achieve remission of malignancy, the ideal timing of transplantation and risk of recurrent malignancy in the setting of immune suppression are also of concern.

In this issue of CJASN, Mansouri et al. (9) leverage the prospective population-based French Renal Epidemiology and Information Network registry that includes patients receiving KRT. The authors identified 287 patients with ESKD attributed to nephrotoxins, chemotherapy, or radiotherapy and 1157 patients with ESKD from urinary tract cancer. Hematologic malignancies were excluded. Also, 11,748 controls without active malignancy were matched to these patients. Both patients with nephrotoxin-related ESKD and patients with urinary tract cancer–related ESKD were more likely to be men and have active malignancy, but they were less likely to be waitlisted for kidney transplant, choose peritoneal dialysis, and have comorbid diseases (cardiovascular or liver disease) compared with matched controls. In patients with urinary tract cancer–related ESKD, nephrectomy was reported as a contributing cause in 50%.

The authors found an overall incidence of 2.22 per million inhabitants (pmi) of cancer-related ESKD, a mean nephrotoxin-related ESKD incidence of 0.43 pmi, and a mean urinary tract cancer–related ESKD incidence of 1.8 pmi. The annual increase of the mean incidence was statistically significant for both groups (nephrotoxin-related ESKD, 5.2% and urinary tract cancer–related ESKD, 1.9%). Two-year mortality in patients with nephrotoxin-related ESKD was greater for those with active malignancy (65%) than for those without (29%), but in the urinary tract cancer–related ESKD group, it was similar (48%) between those with and without active malignancy (9). Furthermore, the urinary tract cancer–related ESKD cumulative incidence of noncancer mortality was comparable across those with (21.9%) and without (24.5%) active malignancy and the control group (25.8%) (9). Mortality risk was greater among those with active malignancy in each group (nephrotoxin-related ESKD subdistribution hazard ratio, 4.2; 95% confidence interval [95% CI], 3.2 to 5.5; urinary tract cancer–related ESKD subdistribution hazard ratio, 2.0; 95% CI, 1.7 to 2.2) in comparison with their control groups, but this was no different for those without active malignancy. Despite similar mortality for patients without active malignancy (in either nephrotoxin-related ESKD or urinary tract cancer–related ESKD) and controls without malignancy, they had significantly longer time to waitlisting (adjusted hazard ratio, 0.62; 95% CI, 0.43 to 0.88 and adjusted hazard ratio, 0.47; 95% CI, 0.36 to 0.60).

There are several important findings that this study highlights. The authors point out that cancer-related kidney disease is increasing, which underscores the value of recognizing the appropriate nephrologic management in the patient with cancer. Urinary tract cancer and then, nephrotoxic injury were the most common causes of ESKD. This is consistent with the finding of high CKD prevalence among patients with RCC. Furthermore, the high nephrectomy rate (50%) in this cohort leading to ESKD calls attention to the potential clinical consequences of the various therapeutic surgical options (such as radical nephrectomy versus nephron-sparing procedures or active surveillance), which clearly affect kidney function. Nephrotoxic cancer therapy contributes to AKI (CKD risk factor). Beyond the traditional chemotherapeutic agents, which have direct tubular toxicity, novel targeted therapies have adverse effects, such as thrombotic microangiopathy (seen with vascular endothelial growth factor inhibitors) or interstitial nephritis (associated with immune checkpoint inhibitors), as well as glomerular pathology, which requires early recognition and precise management to avoid ESKD.

The next key point was the similarity of the adjusted mortality between patients with ESKD without active malignancy and the control patients with ESKD (9), which was unlike the higher mortality seen for the patients with ESKD and active malignancy. Additionally, in Table 2 in reference 9, urinary tract cancer–related ESKD noncancer mortality was the same across all three groups (with and without active malignancy and control). More cancers are discovered incidentally in early stages and are amenable to cure, leading to higher cancer survival. For those with early-stage RCCs (T1 tumors), mortality has been attributed to factors other than cancer. This study further supports such findings.

Perhaps the most important finding of this study was the delay to transplant waitlisting in patients with a history of malignancy but without cancer at the initiation of dialysis. Although several possible reasons for this include pelvic surgeries and radiation, distant organ damage, and concerns over immunosuppression impairing host response to malignant cells, the potential benefits to transplantation for this specific population should be considered. In this cohort, the cause of ESKD consisted largely of RCC (>60%). A prominent RCC subtype in ESKD is papillary RCC, which has more favorable prognostic characteristics compared with clear cell RCC that is primarily seen in the general population. Papillary RCC is often preceded by acquired cystic kidney disease associated with high dialysis vintage. Acquired cystic kidney disease can theoretically regress with gain of kidney function, such as with kidney transplantation (4). Furthermore, kidney function has been associated with urinary tract cancers, where incidence of kidney disease–related cancers rose during periods of kidney function loss (dialysis) and decreased during periods of allograft function (4). Appropriate access to transplantation would further lower cancer incidence and therefore, mortality.

The findings in this study should be considered in the context of a Norwegian study of 377 kidney transplant recipients with a history of malignancy (10). In Norway, the standard waiting period after treatment for malignancy for listing is 1 year as opposed to the 2–5 years used in France and much of the world. Kidney transplant recipients with prior malignancy had no difference in patient or graft survival compared with those without a history of malignancy. This study brings into question the standard 2-year waiting period. A longer waiting period exposes more patients to the morbidity and mortality of dialysis as modality of KRT.

Another important finding of this study is the decreased utilization of peritoneal dialysis compared with matched controls. It is a commonly held myth that patients with malignancy are poor candidates for peritoneal dialysis, but there is no literature supporting this. Furthermore, in the setting of chemotherapy and immunocompromise, peritoneal dialysis may have benefits in avoidance of bloodstream infection, maintaining independence, and transition to palliative care. Further study in this field is warranted.

This study is bolstered by the strengths of the registry population, which includes 100% of individuals in the Lorraine region of France receiving KRT. The longitudinal nature of the study has helped elucidate changes in the epidemiology over time, and lack of censoring for kidney transplant helps understand the nature of transplantation in this population.

Limitations of the study should be considered. The largest limitation is a lack of information regarding the type, grade, and stage of malignancy and the exclusion of hematologic malignancies. Baseline demographic information, such as preexisting CKD or AKI events, is not included. The observational nature of this registry also predisposes to residual confounding and confounding by indication. Malignancy can also result in ESKD for reasons other than nephrotoxins or urinary tract cancer. With a large percentage of patients having nephrectomy as the etiology of ESKD, more information on nephron-sparing surgery would be useful.

Future areas for study may include how cancer stage and the various treatments options may determine outcomes with advanced CKD or ESKD. Additional outcomes, such as cancer recurrence or progression, and further delineation of the cause of mortality (cancer specific, infectious, or cardiovascular disease) may be informative. The ideal timing of transplant remains unknown in patients with a history of malignancy and should be studied prospectively. To better address the increasing incidence of malignancy-related ESKD and the high mortality, pharmacokinetic studies of anticancer therapies in hemodialysis and peritoneal dialysis are drastically needed. Mechanistic studies of increased risk of malignancy in CKD may also provide treatment targets.

To conclude, this observational analysis calls attention to increasing cancer-related kidney failure and associated mortality, but also, it thought provokingly points out the more favorable mortality outcomes in those without active malignancy who will likely benefit from transplantation. Prospective randomized trials are desperately needed to better understand the mechanisms of interplay of CKD and malignancy and better understand the ideal timing of transplantation.

• Copyright © 2020 by the American Society of Nephrology