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Keywords:

  • end-stage renal disease;
  • pathology;
  • prognosis;
  • renal cell carcinoma;
  • transplantation

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Study Type – Prognosis (case series)

Level of Evidence 4

What's known on the subject? and What does the study add?

Patients with end-stage renal disease (ESRD) have an increased risk of developing RCC in their native kidneys. The prevalence of RCC is 3–4% in cases of ESRD in dialyzed and/or transplanted patients, which corresponds to a rate 100-times higher than that in the general population.

This is the first study, to our knowledge, comparing the characteristics of kidney cancer in the ESRD population according to their dialysis or transplantation status at the time of diagnosis. The differences in stage and survival we observed may be due to differences in surveillance strategies between transplanted and not transplanted patients, nevertheless, the differences in pathological subtypes suggest they could also be due to differences in the tumorigenesis process.

OBJECTIVE

  • • 
    To compare clinical, pathological and outcome features of renal cell carcinomas (RCCs) arising in patients with chronic renal failure (CRF) with or without renal transplantation.

PATIENTS AND METHODS

  • • 
    In all, 24 French University Departments of Urology and Kidney Transplantation participated in this retrospective study comparing RCCs arising in patients with CRF according to their dialysis or transplantation status at the time of diagnosis.
  • • 
    Information about age, sex, symptoms, duration of CRF, mode and duration of dialysis, renal transplantation, tumour staging and grading, histological subtype and outcome were recorded in a unique database.
  • • 
    Qualitative and quantitative variables were compared by using chi-square and Student statistical analysis. Survival was assessed by Kaplan–Meier and Cox methods.

RESULTS

  • • 
    Data on 303 RCC cases diagnosed between 1985 and 2009 were identified in 206 men (76.3%) and 64 women (23.7%).
  • • 
    Transplanted and not transplanted patients accounted for 213 (70.3%) and 90 cases (29.7%), respectively.
  • • 
    In transplant recipients, RCC was diagnosed at a younger age [mean (sd) 53 (11) vs 61 (14) years, P < 0.001), the mean tumour size was smaller [3.4 (2.3) vs 4.2 (3.1) cm, P= 0.02), pT1a stage (75 vs 60%, P= 0.009) and papillary histological subtype (44 vs 22%, P < 0.001) were more frequent than in their dialysis-only counterparts.
  • • 
    Nodal (1 vs 6%, P= 0.03) and distant metastases rates (0 vs 5%, P < 0.001) were significantly increased in patients who had not had a transplant. However, Fürhman grading, symptoms, tumour multifocality or bilaterality, presence of acquired cystic kidney disease, were not significantly different between the groups.
  • • 
    Estimated 5-year survival rates were 97% and 77% for transplanted and not transplanted patients, respectively (P < 0.001). In univariate analysis, presence of symptoms (P= 0.008), poor performance status (P= 0.04), large tumour size, advanced TNM stage (P < 0.001), high Führman grade (P= 0.005) and absence of transplantation (P < 0.001) were all adverse prognostic factors. In multivariate analysis, only T stage remained an independent predictor for cancer-related death (P < 0.001).

CONCLUSION

  • • 
    RCC arising in native kidneys of transplant patients seems to exhibit many favourable clinical, pathological and outcome features compared with those diagnosed in dialysis-only patients. Further research is needed to determine whether it is due to particular molecular pathways or to biases in relation to mode of diagnosis.

Abbreviations
ACKD

acquired cystic kidney disease

CRF

chronic renal failure

ESRD

end-stage renal disease.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Patients with end-stage renal disease (ESRD) have an increased risk of developing RCC in their native kidneys. The prevalence of RCC is 3–4% in cases of ESRD in dialyzed and/or transplanted patients, which corresponds to a rate 100-times higher than that in the general population [1] and this risk increases with duration of dialysis [2]. The statistical work of Heinz-Peer et al. [1] and Hoshida et al. [3] showed that acquired cystic kidney disease (ACKD) is an independent risk factor for kidney cancer. The prevalence of ACKD was also directly related to the duration of dialysis [4]. Some recent studies have shown that most RCCs in renal-transplant recipients are incidental low-stage, low-grade tumours with favourable prognosis. The outstanding pathological findings are bilateral occurrence, papillary subtype and multifocality [5,6]. However, these studies involve few patients, which limit their scientific value. Moreover, the outcome of the ACKD after transplantation and the influence of immunosuppression have not been clearly determined, although it appears that ACKD regresses after transplantation [4]. The Oncology Committee and the Transplantation Committee of the French Urological Association have decided to jointly conduct a survey to identify cases of RCC in patients with ESRD. The objective was to compare clinical, pathological and outcome features of RCC arising in patients with ESRD according to their dialysis or transplantation status at the time of diagnosis.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

This was a retrospective study including data from 24 centres in France. After approval by Institutional Review Board in all centres, records of patients who had a RCC arising in the context of ESRD who underwent a renal transplantation or not were reviewed. The following variables were assessed and were recorded in a unique database: age, sex, body mass index, history of hypertension, symptoms at diagnosis, duration of ESRD, mode and duration of dialysis, renal transplantation, tumour staging and grading, histological subtype and outcome. In all, 303 RCC cases were identified between July 1985 and April 2009 in 206 men (76.3%) and 64 women (23.7%). Tumour stage was determined according to the 2002 TNM classification [7]. Histological subtype was recorded according to the 2004 WHO classification [8]. Tumours were graded according to the Führman grading scheme by pathologists at each institution [9]. The endpoint of interest was the role of transplantation. Patients' characteristics in both the transplanted and not transplanted groups were compared by using chi-squared (or Fisher) and t-tests for qualitative and quantitative variables, respectively. The Cox proportional hazards model was used for investigating time to the event occurrence. In the univariate analysis, a P < 0.05 was used to select explanatory variables for the multivariate analysis. A backwards elimination was used to select clinical and pathological features independently associated with chronic renal failure (CRF). Results were given as hazard ratios with 95% CIs. A P < 0.05 was considered to indicate statistical significance. The model validity was verified by testing the risk proportionality hypothesis for the variable present in the final model. Patient's survival was defined as the time between the date of surgery and the date of cancer-specific death. Patients alive after their last follow-up were censored.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Transplant and not transplant patients accounted for 213 (70.3%) and 90 patients (29.7%), respectively. Clinical features of the groups are compared in Table 1. In transplant patients, RCC cases occurred at a mean (sd) of 91 (82) months after transplantation. The pathological features of the groups are compared in Table 2. Six patients (3%) and 21 patients (23%) died from RCC in the transplant and not transplant groups, respectively. The median (range) follow-up for this population was 36 (1–277) months. The 5-year progression-free survival was 88% in transplanted patients and 52% in not transplanted patients (log-rank P < 0.001; Fig. 1). The 5-year cancer-specific survival was 97% in transplanted patients and 77% in not transplanted patients (log-rank P < 0.001; Fig. 2). In univariate analysis, presence of symptoms (P= 0.008), poor performance status (P= 0.04), large tumour size, advanced TNM stage (P < 0.001), high Führman grade (P= 0.005) and absence of transplantation (P < 0.001) were all adverse prognostic factors for cancer-related death. In multivariate analysis, only T stage remained an independent predictor for cancer-related death (P < 0.001).

Table 1. Clinical features comparison
VariableTransplantedNot transplanted dialysis only P
  1. ECOG PS, Eastern Cooperative Oncology Group Performance Status.

No. of patients21390 
Mean (sd) age at RCC diagnosis, years53 (11)61 (14)<0.001
Male percentage76770.80
Mean (sd) body mass index, kg/m224.7 (5.1)25.9 (6.6)0.16
History of hypertension, %77830.28
Mean (sd) age at ESRD diagnosis, years40 (13)51 (14)<0.001
Mean (sd) duration of exposition to ESRD, months162 (88)120 (84)<0.001
Mean (sd) duration of dialysis, months123 (91)82 (79)<0.001
Symptoms at diagnosis, %10170.10
ECOG PS ≥ 1, %1539<0.001
Nodal metastases at diagnosis, n (%)2 (1)5 (6)0.03
Distant metastases at diagnosis, n (%)04 (5)<0.001
Table 2. Pathological features comparison
VariableTransplantedNot transplanted dialysis only P
No. of patients21390 
Mean (sd) tumour size, cm3.4 (2.3)4.2 (3.1)0.02
Stage, n (%)   
 pT1a160 (75)54 (60)0.009
 pT1b28 (13)16 (18)0.25
 pT211 (5)7 (8)0.38
 pT3a4 (2)7 (8)0.01
 pT3b10 (5)4 (4)0.91
 pT402 (2)0.16
Führman grade, n (%)   
 110 (13)11 (12)0.92
 243 (55)48 (54)0.81
 324 (31)27 (30)0.91
 43 (1)3 (4)0.14
Histological subtype, n (%)   
 Clear cell107 (50)69 (77)<0.001
 Papillary94 (44)20 (22)<0.001
 Chromophobe9 (4)1 (1)0.22
 Others3 (2)00.25
Tumour multifocality, n (%)48 (23)26 (29)0.27
Tumour bilaterality, n (%)57 (27)20 (22)0.41
Presence of ACKD, n (%)121 (57)55 (61)0.49
image

Figure 1. Progression-free survival.

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image

Figure 2. Specific survival.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

This is the first study, to our knowledge, comparing the characteristics of kidney cancer in the CRF population according to their dialysis or transplantation status at the time of diagnosis. In the present study, cumulating 303 RCC cases, cancers arising in native kidneys of transplanted patients seem to exhibit many favourable clinical, pathological and outcome features than those diagnosed in dialysis-only patients. The main hypothesis to explain these findings is a difference in the precocity of the diagnosis [6]. Transplanted patients were younger [mean (sd) age of 53 (11) vs 61 (14) years, (P < 0.001)], had smaller tumours [mean (sd) 3.4 (2.3) vs 4.2 (3.1) cm, P= 0.02] and the frequency of stage pT1a was higher (75 vs 60%, P= 0.009) than in patients on dialysis. Moreover nodal (1 vs 6%, P= 0.03) and distant metastases rates (0 vs 5%, P < 0.001) were significantly higher in dialysis-only patients. Transplanted patients were likely to have their native kidneys monitored by a surgeon more frequently than dialysis-only patients. In most French centres, surgical monitoring of renal transplant patients is performed by urologists, while dialysis patients are followed by nephrologists. Earlier diagnosis of the RCC in transplanted patients may then account for the lower specific mortality.

However, the present study showed that the cancers were not histologically similar. Transplanted patients more frequently had papillary RCC (44 vs 22%, P < 0.001) and less frequently clear cell RCC (50 vs 77%, P < 0.001). ACKD has been reported as being associated with a particular histological subtype of RCC: the ‘clear-cell papillary RCC of the end-stage kidneys’[10]. In the present study, the frequency of ACKD was not different between the groups (57 vs 61%, P= 0.49). However, the duration of exposure to ESRD [mean (sd) 162 (88) vs 120 (84) months, P < 0.001] and dialysis [123 (91) vs 82 (79) months, P < 0.001] was longer in transplanted patients. In addition, the age at diagnosis of ESRD was older among not transplanted patients [mean (sd) 51 (14) vs 40 (13) years, P < 0.001]. Previous studies have shown that the greater the duration of ESRD, the greater the risk of developing RCC [2]. The present study showed that longer the exposure to ESRD, the more frequent ‘the clear-cell papillary RCC of the end-stage kidneys’ and the better the prognosis. In dialysis-only patients, the RCCs possibly have characteristics closer to sporadic RCCs because they were less frequently specific of CRF patients. The main limitation of the present study is related to its retrospective design and the inability to perform a centralised review of pathological samples. However, the centres that participated in the present study are all university departments that ensure a good level of competence of pathologists.

In conclusion, RCC in the native kidney of transplant patients seem to exhibit many favourable clinical, pathological and outcome features compared with those diagnosed in dialysis-only patients. Cancer-specific survival was better for transplant than dialysis-only patients. T stage was the sole statistically significant independent prognostic factor for RCC in the context of ESRD. It is of course possible that the differences in stage and survival we observed are due to differences in surveillance strategies between transplanted and not transplanted patients, nevertheless, in the present study, the differences in pathological subtypes suggest they could also be due to differences in the tumorigenesis process.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES