Transplantation: Research Article Am J Nephrol DOI: 10.1159/000510616

Received: June 12, 2020 Accepted: August 8888 1, 2020 Published online: September 30, 2020

Characteristics and Graft Survival of Kidney Transplant Recipients with Renal Cell Carcinoma Rushad Machhi a Didier A. Mandelbrot a Talal Al-Qaoud b, c Brad C. Astor a, d Sandesh Parajuli a  

 

 

 

 

aDepartment

of Medicine, Division of Nephrology, University of Wisconsin School of Medicine and Public Health, Wisconsin, Madison, WI, USA; bDepartment of Surgery, Division of Transplant Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; cDepartment of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; dDepartment of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

Abstract Background: The incidence of renal cell carcinoma (RCC) is higher in kidney transplant recipients (KTRs) compared to the general population. However, the risk factors and outcomes based on the diagnosis of RCC after kidney transplantation are limited. Methods: We analyzed risk factors for the development of RCC in KTRs transplanted at our institution between 1994 and 2016. We compared the incidence of graft failure and mortality in KTRs with RCC to matched controls using 5:1 event density sampling. Identifying the risk factors of RCC and patient and graft survival were outcomes of interest. Results: There were 4,178 KTRs performed at our institution during the study period, and 51 patients were diagnosed with RCC. Recipients were followed until graft failure or death. We did not identify commonly looked at baseline characteristics associated with the risk of RCC. Comparing KTRs with RCC to matched controls, RCC patients were younger (47.5 vs. 49.6 years, p < 0.01), received basiliximab

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© 2020 S. Karger AG, Basel

induction more commonly (p = 0.01), had hypertension and glomerulonephritis as causes of end-stage renal disease (p = 0.01), and were more likely to be smokers (p < 0.01). RCC was significantly associated with death-censored graft failure (adjusted hazard ratio [HR]: 1.76; 95% CI: 1.02–3.03; p = 0.04) but not patient death (adjusted HR: 0.95; 95% CI: 0.50–1.83; p = 0.89). Conclusion: In our experience, RCC had a detrimental impact on graft survival among KTRs, highlighting the potential benefit of early diagnosis and optimal immunosuppression management in optimizing graft survival. © 2020 S. Karger AG, Basel

Introduction

Kidney transplantation is the best treatment for patients with end-stage renal disease (ESRD), offering up to an 80% reduction in mortality compared to remaining on dialysis [1]. Patients who receive a kidney transplant on average double their life expectancy compared to those who remain on the waitlist [2]. These recipients are also at a higher risk of complications associated with the use of chronic immunosuppression. Malignancy has been Sandesh Parajuli Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, UW Medical Foundation Centennial Building 4175 1685 Highland Avenue, Madison WI 53705 (USA) sparajuli @ medicine.wisc.edu

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Keywords Renal cell carcinoma · Kidney transplant · Graft survival · Immunosuppressed

Materials and Methods Study Population and Design All adult KTRs transplanted at the University of Wisconsin between January 1, 1994, and December 31, 2016, were included. This study was approved by the Health Sciences Institutional Review Board at the University of Wisconsin. We first investigated factors of all KTRs and those who were diagnosed with biopsy-proven RCC after transplantation. Subsequently, we analyzed the outcomes of those diagnosed with RCC and compared them to a matched control group using event density sampling at a 1:5 ratio. Controls were matched for sex, race (Caucasian or non-Caucasian), prior transplant, and the decade of age. We included all subtypes of RCC into this definition. Recipients were followed until death or graft failure, whichever occurred first. Factors Examined and Definitions Baseline demographics for all patients and those with posttransplant RCC included age at transplantation, time to RCC diagnosis, sex, race, cause of ESRD, time on dialysis before transplantation, living donor percentage, retransplant percentage, and type of immunosuppressive induction agents. Risk factors such as smoking status and BMI were also investigated. Cigarette smoking status was stratified by the current smoker, former smoker, and never smoker. Death and death-censored graft failure were outcomes of interest, along with the risk factors for RCC.

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Table 1. Baseline characteristics among all kidney recipients

during the study period

Baseline characteristics Kidney recipients, n 4,178 Mean age at transplant, years±SD 49.2±0.2 Male, n (%) 2,505 (60.0) Race, n (%) Caucasian 3,456 (83.7) Non-Caucasian 682 (16.3) Cause of ESRD, n (%) Diabetes 1,078 (25.8) Hypertension 447 (10.7) Glomerulonephritis 495 (11.8) Polycystic kidney disease 944 (22.6) Others 1,214 (29.1) Time on dialysis before treatment, months (IQR) 20 (10, 39) Living donor transplant, n (%) 1,633 (39.0) Retransplant, n (%) 667 (16.0) Induction immunosuppressive, n (%) Antithymocyte globulin 983 (23.5) Alemtuzumab 721 (17.2) Basiliximab 1,881 (45.0) OKT3 270 (6.5) Others 323 (7.7) ESRD, end-stage renal disease.

RCC Screening Protocol There is no standard posttransplant RCC screening protocol at our institution. All RCCs were diagnosed either after a workup for symptoms or incidentally after radiological evaluation of the abdomen and pelvis for some other indication and confirmed histologically either by biopsy or pathology from nephrectomy. Induction and Maintenance Immunosuppressive Medications Patients undergoing kidney transplants received induction immunosuppression with a depleting agent (antithymocyte globulin, alemtuzumab, or OKT3) or nondepleting agent (basiliximab or daclizumab) based on immunological risk factors as previously described [8]. Patients were typically maintained on a triple immunosuppressive regimen with a calcineurin inhibitor (predominantly tacrolimus), antiproliferative agent (mainly, mycophenolate mofetil or mycophenolic acid), and steroids. Some patients had early steroid withdrawal, based on the patient’s request and clinical judgment. Doses and drug levels were individually adjusted at physician discretion based on the patient’s clinical condition, including infection, malignancy, and rejection. Switching to the mammalian target of rapamycin inhibitors after the diagnosis of RCC is not a common practice in our institution. Statistical Analysis Competing-risks regression analysis for univariate and multivariate analyses of our baseline characteristics were used to assess risk factors that were associated with the incidence of RCC in KTRs. We used event density sampling to match each RCC patient with KTRs without RCC as described above. We at-

Machhi/Mandelbrot/Al-Qaoud/Astor/ Parajuli

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identified as the third leading cause of mortality in kidney transplant recipients (KTRs) after cardiovascular disease and infection [3]. The risk for most solid cancers is increased after kidney transplantation. Among solid tumors, the relative risk of renal cell carcinoma (RCC) is one of the highest, with 3- to 15-fold increase in the risk compared to the general population [4]. While the increased risk for RCC among transplant recipients has been well documented, consensus and guidelines for screening using demographic characteristics and comparative outcomes of KTRs with RCC are not well established. Chewcharat et al. [5] in a meta-analysis found that mortality following RCC in KTRs was 15% at an average follow-up of 42 months. However, the studies used to compile this meta-analysis did not compare survival outcomes to matched controls [5]. Karami et al. [6] found that RCC risk was elevated in US renal transplant recipients with the following characteristics: African American, male, longer pretransplant dialysis treatment, certain induction agents, polycystic kidney disease, hypertensive nephrosclerosis, and vascular disease [6]. Acquired cystic kidney disease is another important risk factor in the development of RCC [7]. Here, we attempt to further identify risk factors associated with the development of posttransplant RCC and its effect on graft survival and patient survival.

Table 2. Characteristics of KTRs with RCC

Baseline characteristics Patients, n Median interval from transplant to RCC, years (IQR) RCC in native kidney RCC in graft RCC in both native kidney and graft Metastatic presentation Mean age at transplant, years±SD Male, n (%) Race, n (%) Caucasian Non-Caucasian Cause of ESRD, n (%) Diabetes Hypertension Glomerulonephritis Polycystic kidney disease Others Time on dialysis before treatment, months (IQR) Induction immunosuppressive, n (%) Antithymocyte globulin Alemtuzumab Basiliximab OKT3 Others Risk factors, n (%) Current smoker Former smoker Mean BMI (±SD) RCC histology, n (%) Clear cell Papillary Mixed: clear cell and papillary Others

51 6.16 (2.56, 12.08) 40 9 2 2 47.5±1.9 33 (64.7) 40 (78.4) 11 (21.6) 8 (15.7) 10 (19.6) 16 (31.4) 4 (7.8) 13 (25.5) 14 (6–39) 11 (21.6) 5 (9.8) 24 (47.1) 6 (11.8) 5 (9.8) 5 (9.8) 16 (31.4) 26.1±0.7 19 (37.3) 21 (41.2) 9 (17.6) 2 (3.9)

KTR, kidney transplant recipient; RCC, renal cell carcinoma; ESRD, end-stage renal disease.

Renal Cell Carcinoma in Kidney Transplant Recipients

Results

The baseline characteristics of our transplant recipients are presented in Table  1. Of the 4,178 KTRs, 51 (1.2%) developed RCC. Baseline characteristics for these 51 patients are in Table 2. The primary cancer was found to be in the native kidney in 40 of these cases (78%), 9 recipients had RCC in the allograft (18%), and 2 had metastatic RCC at presentation (4%). Clear cell and papillary histology were the dominant subtypes, accounting for 37.3 and 41.2% of cases, respectively. The incidence of RCC steadily rose after transplantation, as shown in Figure 1. Table 3 compares baseline characteristics and risk factors between the 51 patients with RCC and the remaining Am J Nephrol DOI: 10.1159/000510616

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tempted a ratio of 1:5, and this was possible for 44 RCC patients. 1 RCC patient was matched to 4 controls, 3 RCC patients were matched to 3 controls, 1 RCC patient was matched to 2 controls, and 2 RCC patients were matched to 1 control each. Thus, the 51 cases of RCC were matched to 237 controls. Baseline characteristics and risk factors were compared between these 2 groups. χ2 testing was used for categorical data while Student t testing was used for continuous data. Kaplan-Meier curves were used comparing graft survival and patient survival between KTRs with RCC and matched controls. Unadjusted and adjusted hazard ratios comparing the incidence rate of death and graft failure between KTRs with RCC and matched controls without RCC were calculated using multivariable Cox proportional hazard regression models. Adjusted hazard ratios were calculated by controlling the entire baseline demographics mentioned above. Among patients with recurrence or multiple RCC, only the first case was used for the analysis.

Proportion developing renal cell carcinoma

0.05 0.04 0.03 0.02 0.01 0 0

1

2

3

4

5

6

Follow-up time, years

7

8

9

10

Fig. 1. Incidence of RCC in our KTRs.

Table 3. Univariate and multivariate analyses for risk of RCC in KTRs (incident carcinoma)

Variable

Factors associated with RCC Non-Caucasian Female Thymoglobulin Basiliximab OKT3 Alemtuzumab Retransplant Diabetes Polycystic kidney disease Hypertension Glomerulonephritis Age (/per 10 years) Living donor transplant Pretransplant dialysis (/yr) Current smoker Former smoker BMI

Univariate analysis

Multivariate analysis

HR

95% CI

p value

HR

95% CI

p value

2.20 0.85 1.00 1.64 0.79 0.92 1.12 1.00 2.82 1.04 2.00 0.99 1.15 1.20 2.12 1.40 0.98

1.12–4.33 0.48–1.51 Ref. 0.79–3.40 0.28–2.20 0.32–2.70 0.54–2.30 Ref. 1.11–7.17 0.31–3.45 0.85–4.70 0.80–1.23 0.66–2.00 0.62–2.35 0.82–5.47 0.76–2.58 0.93–1.04

0.02 0.57 – 0.18 0.65 0.88 0.76 – 0.03 0.95 0.11 0.94 0.61 0.59 0.12 0.27 0.49

2.01 0.89 1.00 0.86 0.96 0.97 1.37 1.00 1.11 2.07 1.20 1.02 1.33 1.15 1.83 0.98 0.98

0.96–4.20 0.49–1.60 Ref. 0.30–2.41 0.32–2.95 0.32–2.95 0.64–2.94 Ref. 0.33–3.78 0.86–4.97 0.49–2.97 0.81–1.29 0.71–2.47 0.57–2.35 0.70–4.74 0.92–1.03 0.93–1.04

0.06 0.69 – 0.77 0.94 0.96 0.42 – 0.87 0.10 0.69 0.85 0.37 0.69 0.22 0.42 0.49

RCC, renal cell carcinoma; KTR, kidney transplant recipient; HR, hazard ratio.

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KTRs with RCC were found to be younger than matched controls with RCC (47.5 ± 13.2 vs. 49.6 ± 13.2, respectively, p < 0.01) (Table  4). Median follow-up of RCC patients and matched controls was 10.36 years (IQR: 6.60–14.80). Those with RCC differed from controls in terms of induction agents used (p = 0.01), with basilixMachhi/Mandelbrot/Al-Qaoud/Astor/ Parajuli

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KTRs without RCC. Being non-Caucasian (HR: 2.20; 95% CI: 1.12–4.43; p = 0.02) and having polycystic kidney disease (HR: 2.82; 95% CI: 1.11–7.17; p = 0.03) had an association with an increased risk of RCC. However, after adjustment in the multivariate analysis, none of these variables were associated with the development of RCC.

1.00

Control

0.90

Proportion surviving

0.80

p = 0.25

Renal cell carcinoma

0.70 0.60 0.50 0.40 0.30 0.20 0.10 0 0

1

2

Fig. 2. Death-censored graft survival com-

3

4

5

6

Follow-up time, years

7

8

9

10

paring RCC and control.

imab being more common (47.1 vs. 38.0%) in KTRs with RCC than KTRs without RCC. Those with RCC also differed in terms of the primary cause of ESRD (p = 0.01), with hypertension (19.6 vs. 14.3%) and glomerulonephritis (31.4 vs. 24.1%) being common causes in KTRs with RCC than KTRs without, while diabetes (15.7 vs. 22.8%) was less common. Former smokers (31.4 vs. 24.1%) and current smokers (9.8 vs. 6.3%) were more common in the RCC group. In unadjusted Kaplan-Meier analysis, RCC was not associated with an increased risk of death-censored graft failure when compared to matched controls (p = 0.25) (Fig. 2). This was further investigated by Cox regression analysis (Table 5). In unadjusted analysis, there was a 55% higher risk of death-censored graft failure (HR: 1.55; 95% CI: 0.92–2.63; p = 0.10), although not statistically significant. However, after adjustment for baseline characteristics, the risk increased to 76% and was statistically significant (HR: 1.76; 95% CI: 1.02–3.03; p = 0.04). None of the 9 cases of primary RCC in the transplanted kidney needed graft nephrectomy due to RCC. Similarly, in an unadjusted Kaplan-Meier analysis, RCC was not associated with mortality (p = 0.12) (Fig. 3). This was further investigated by Cox regression analysis (Table  5). In unadjusted (HR: 0.66; 95% CI: 0.39–1.11; p = 0.12) or after adjusting for baseline characteristics, RCC was still not statistically significant (HR: 0.95; 95% CI: 0.50–1.83; p = 0.89) for mortality.

Table 4. Comparison of risk factors in KTRs with and without RCC

Renal Cell Carcinoma in Kidney Transplant Recipients

Am J Nephrol DOI: 10.1159/000510616

using event density sampling

Variable Factors associated with RCC Number Mean age (years±SD) Non-Caucasian, % Female, % Pretransplant dialysis, % Living donor, % Retransplant, % Mean BMI, % Induction agent, % Anti-thymocyte globulin Basiliximab OKT3 Alemtuzumab Others Cause of ESRD, % Diabetes mellitus Hypertension Polycystic kidney disease Glomerulonephritis Others Smoking status, % Never smoker Former smoker Current smoker

RCC

Control

p value

51 47.5±13.2 21.6 35.3 78.4 47.1 17.6 26.1

237 49.6±13.2 21.5 34.2 75.1 41.8 17.7 26.6

–