The demographics of our cohort are similar to that of previous studies in terms of age, gender (10–14,19–21), mean follow up period 7.5 to 10 years (5,11–14,20,21), prevalence of hypertension and diabetes (10–12,14,20,21), indication for RC bladder cancer (10–12,14,19,20), with stages T≥2 from 63 to 78% (12,20,21). Therefore, our study is comparable to these previous reports.
We found that the majority of patients experienced a decrease in kidney function during long-term follow up. The initial eGFR in our cohort was 65.8 ml/min/1.73m2, which is similar to previous reports (10,12–14,20) with initial eGFR ranging from 65 to 69.7 ml/min, with the exception of Samuel et al, which reported an eGFR of 77. This was most likely due to the fact that the cohort in Samuel et al was younger. The eGFR after two years was 55 ml/min, again similar to previous reports with ranges from 55 to 59 (11–14,20), being comparable. 62.8% of patients had a decline of their kidney function during follow up, and 32.8% of patients had a decrease of >10 ml/min/1.73m2 at 2 years. Previous studies have shown a high prevalence 70% (11,21) at 10 years, and 49% at 5 years (11), however there are also reports with a lower prevalence 34 to 51% (12–15). The difference in the prevalence across the different studies could be explained by the variety in definitions used to categorize the decline in kidney function, as well as different follow up times, and different methods of GFR estimation.
There is a predictable decline in the kidney function related to aging; the annual age-related decline in eGFR from age 30 years onward is believed to be ±1 mL/min/1.73 m2 in a healthy population (22–24). This GFR declines by about 8 – 10 ml/min/1.73 m2 per decade (25,26), however a linear decline in eGFR over time is often observed (27) in patients with diabetes or HTN. This decline in persons with diabetes can range from ±2-3 mL/min/1.73m2 per year (28). In patients with RC and ICD, previous reports have used definitions such as a decrease of 1 ml/min/year (5,11,12) over a time period of 5 to 10 years, a decrease of >25% (15,20) in eGFR from baseline, or a decline of >10% in eGFR (11,14). The definition of a clinically significant deterioration in kidney function in our study was a decrease of >10 ml/min/1.73m2 in the first two years. This was selected because the majority of the observed decline in kidney function in previous studies occurs in the first 2 years (12,20). This represents the period of major risk for kidney function deterioration, which is likely associated with RC and of clinical significance.
A further difference relates to the method used to measure kidney function in patients with RC. The most common methods used are the MDRD (12,14,19), CKD-EPI equations (10,11) and isotopic (5,19) methods. These equations represent a practical way to measure kidney function, which is reliable, easy to use and reproducible. The gold standard to measure GFR is the use of isotopes or inulin; these methods are costly and not widely available in clinical practice. There are reports that suggest that methods like MDRD and CKD-EPI overestimate the GFR comparing this with isotopic methods (19) in patients post RC. Therefore, the differences between these series can be explained by variations in patient selection and the variety of methods used to calculate eGFR.
The use of estimated methods to assess the kidney function have some caveats and considerations. One important consideration is that these equations are dependent on the level of serum creatinine; the level of which reflects kidney function but serum creatinine can also be affected by muscle mass, weight, diet, exercise and other possible factors (29,30). For example, a decrease in body weight after a diagnosis of cancer is a frequent phenomenon, Meyerhardt et al, previously reported a decrease in 37.5% of patients (31). On the other hand, it is unclear whether there is significant reabsorption of urea and creatinine in ICD patients, as the contact time of urine is shorter and the reabsorbing surface of an ICD is small. Animal models suggest that much of the creatinine is reabsorbed by solvent drag, a glucose-dependent way of transport. Creatinine is reabsorbed less well by an active carrier mediated transport. As urine normally does not have large amounts of glucose, creatinine may be resorbed to a lesser degree (32).
It should be noted that changes in kidney function were not uniform across patients, in our analysis we showed that 36.7% of our patients has stable or mild increase in their eGFR, and 10.6% an increase of >10%, since previous reports showed similar findings Rouanne (12) et al 26%, Gondo (10) et al 56%. The presence of clinical or subclinical urinary obstruction (5) can affect kidney function, and release of the ureteral obstruction could lead to an improvement in kidney function (5,10).
Our study showed cumulative incidence of dialysis of 5.6% at 5 years; Jin et al (14), reported only 1.2% and Rouanne (12) et al only 2.5%. The low incidence in the Jin (14) et al report may be related to a younger cohort and patient selection. Additionally, the incidence of dialysis may be affected by high mortality since there is a higher incidence of comorbidity, and conservative treatment may have been adopted rather than dialysis..
Long-term kidney function after RC can be adversely affected by several factors, including age, potential nephrotoxic chemotherapy, comorbidities, and urine diversion-related factors. Our results are concordant with previous studies, in that age and preoperative eGFR associated significantly with postoperative kidney function on both univariate and multivariate analyses (11,12,33). However, there is not a clear consensus about other risk factors; neither chronic hypertension nor diabetes mellitus were associated with the decline eGFR (10,12,20,33), or different types of ureterointestinal anastomoses, such as Bricker and Wallace (12,33) or urinary infection (12), or chemotherapy (20,33). Nonetheless, other reports have shown associations with HTN (5,11,14), Diabetes (14), hydronephrosis post RC (11), urinary infection (5,11,14) and total subcutaneous fat (10).
While mortality at 10 years in the other cohorts was from 59 to 65% (12,14) in our study it was 76.5%. After adjustment in multivariate analysis the main risk factors associated were age, pre operative eGFR and sex. The lack of association with previous well-known risk factors like HTN and DM are most likely related to the follow up, the nature of the cancer and a high mortality rate, that have a high impact as a competing event.
The present study is limited by its retrospective nature, and nonrandomized design and the single centre design may be associated with unknown biases. Additionally, we could not include well-known other clinical factors such as nutrition status due to unavailability of this data. Excluding patients without complete data may have introduced selection bias. Despite these limitations, we have analysed a significant number of patients, with regular follow up, and have confirmed mortality and dialysis status with the National Cancer Centre Office and the National Kidney Registry databases which are regularly updated and maintained prospectively. We did not evaluate the gold standard measures of inulin clearance or use of isotope measured GFR, and while we recognise the potentially limited accuracy of measuring serum creatinine in this cohort, the use of the eGFR is the standard clinical practice due to simplicity, cost and availability, and eGFR is mainly used for management and therapeutic approach in clinical practice.