The incidence and risk factors of chronic kidney disease after radical nephrectomy in patients with renal cell carcinoma

doi:10.21203/rs.3.rs-1604368/v1

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The incidence and risk factors of chronic kidney disease after radical nephrectomy in patients with renal cell carcinoma

https://doi.org/10.21203/rs.3.rs-1604368/v1

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Background: Radical nephrectomy (RN) is the standard treatment for localized renal cell carcinoma. The decrease of nephrons by the RN could lead to postoperative chronic kidney disease(CKD). The study aims to investigate the incidence and risk factors of CKD in patients who had received RN.

Methods: A Total of 1233 patients were diagnosed with renal cell carcinoma and underwent radical nephrectomy in Zhejiang Provincial People’s Hospital from January 2010 to December 2018. Those who had abnormal renal function before surgery or lost to follow-up were excluded. 500 patients were enrolled in the end. eGFR was calculated using the abbreviated MDRD equation. CKD was defined as eGFR less than 60 ml/min/1.73m². Incidence of postoperative CKD was estimated using the Kaplan-Meier method. The independent risk factors of the occurrence of CKD was determined through logistic multivariate regression analysis.

Results: Patients were followed up for a median of 40 month (3-96 months), with CKD occurred in 189 cases. 5-year cumulative incidence of CKD was 43.4%. There was a significant difference between these 189 patients and the rest patients without post nephrectomy CKD in terms of age, sex, weight, preoperative eGFR(P＜0.05). Multivariate regression analysis shows that age (OR=1.038, 95%CI=1.002-1.076), preoperative eGFR of the contralateral kidney (OR=0.934, 95%CI=0.884-0.988) and postoperative eGFR (OR=0.892, 95%CI=0.854-0.931) were independent risk factors for postoperative CKD.

Conclusions: The incidence of CKD after radical nephrectomy was not uncommon. Age, preoperative eGFR of the contralateral kidney and postoperative eGFR are independent risk factors for postoperative CKD.

Prognosis

Renal cell carcinoma

Radical nephrectomy

Renal dysfunction

Radical nephrectomy (RN) is the historically and standard treatment for localized renal cell carcinoma (RCC)¹. However, the likelihood of decline in kidney function after kidney cancer surgery is an important consideration when treating patients with a renal mass. It has been proved that the decrease of nephrons by the RN could lead to postoperative chronic kidney disease(CKD)². According to the guideline of Kidney Disease Outcome Quality Initiative (K/DOQI)³, CKD was defined as glomerular filtration rate (GFR) or estimated GFR (eGFR) less than 60 mL/min per 1.73 m².There is increasing concern that surgically induced CKD will be associated with an increased risk of hospitalization, cardiovascular events, and death, as has been shown in CKD from all causes. As far as we know, long-term follow-up data of the incidence of CKD in patients post RN was rare. In this study, we sought to determine postoperative long-term changes in renal function after RN in patients with RCC.

The clinical data of 1233 renal cell carcinoma patients who received radical nephrectomy were collected from Jan. 2010 to Dec. 2018. All patients were from Zhejiang Provincial People’s Hospital. Institutional Review Board approval was obtained from the Ethics Committee of Zhejiang Provincial People’s Hospital. Patients who had preoperative metastatic disease or preoperative CKD (GFR＜60ml/min/1.73m²) and those whose follow-up were less than 3 months were excluded. A total of 500 patients were enrolled in our study group, including 421 cases of clear cell carcinoma, 17 cases of papillary cell carcinoma, 20 cases of chromophobe cell carcinoma, 4 cases of acidophile cell adenoma and 38 cases of other pathology types.

Demographic and clinical information such as age, sex, weight, height, profession, BMI, hemoglobin, urine protein, blood lipids, pathology grade were collected for analysis. Also, the past history of smoking, hypertension, diabetes, renal disease, and other clinical characteristics possibly related to CKD were also collected. Serum creatinine (Scr) was used to calculate eGFR, with preoperative GFR being measured by dynamic renal scintigraphy. Stage of disease was reviewed by two independent clinicians using 2010 American Joint Committee on Cancer (AJCC) TNM classification. Estimated GFR (eGFR) were calculated by abbreviated Modification of Diet in Renal Disease (MDRD) equation recommended by K/DOQI guideline⁴ to replace actual value of GFR, with the equation as “eGFR=175×(Scr)^-1.154×(age)^-0.203×(female×0.742), Scr (mg/dl),1mg/dl=88.4μmol/L, age (year old)”. Chronic kidney dysfunction, according to K/DOQI guideline, was defined as GFR＜60ml/min/1.73m²for more than three months.

The postoperative incidence of CKD was calculated by Kaplan-Meier analysis and the life tables. The χ2, Student t and rank sum test were used to compare differences in qualitative and quantitative variables between patients with CKD (CKD group) and those without CKD (no-CKD group). The independent risk factors of the occurrence of CKD was determined through logistic multivariate regression analysis. P values were 2-sided with a P＜0.05 being defined as significant. Data analysis was conducted with IBM SPSS statistics 24.0 (SPSS, Inc, Chicago, IL)

Patients were followed up for 3-96 months, with the median followup of 40 months. 189 patients developed postoperative CKD, with the 5-year cumulative incidence of CKD was 43.4%. Most cases of CKD, as observed, occurred within 1 year after surgery, with median interval of 3 months. The cumulative incidence of CKD at 3 months, 1 year, 3 years and 5 years after surgery was 23.2%, 36.0%, 41.4% and 43.4% respectively.

We found that latent CKD occurred in 36(19%) patients whose eGFR were normal at first follow up visit. On the other hand, improvement of renal function over time was also observed in our cohort. 130 patients were found to have CKD at the first follow-up visit (3 months after surgery), 40 cases in these patients have an improvement of eGFR to normal during subsequent visits. It is worth noting that 37 of these 40 patients’ eGFR value were above 50ml/min/1.73m²when CKD was observed during the follow-up, and only 3 patients’ eGFR dropped to the level of 40-50ml/min/1.73m². 23 patients (13.3%) with normal immediate postoperative eGFR would develop CKD within 5 years. About 95(50%) patients developed CKD if the contralateral kidney eGFR was less than 40ml/min/1.73m², and the probability will increase to 70% if the contralateral kidney eGFR value was less than 30ml/min/1.73m². Among all 500 patients, 155 patients were followed up for more than 6 years, among whom, if CKD did not occur within 5 years, no patients developed CKD afterwards.

We studied the cumulative incidences of CKD of different level of preoperative contralateral GFR values, with the 5-years cumulative incidence of CKD as 72.0%, 57.8%, 27.5% and 24.5% respectively (Fig 1). As for different age levels, the 5-years cumulative incidence of CKD was 19.8%, 42.1%, 51.4% and 77.7% respectively (Fig 2). Incidence of CKD would be increased with the increase of the tumor size, with the 5-years cumulative incidence of CKD as 42.6%, 44% and 31.7% for T1a, T1b and T2 stage respectively (Fig 3).

When comparing the difference between patients with CKD (CKD group) and patients without CKD (no-CKD group), univariate analysis showed that these two groups were apparently different in variables including age, sex, weight, preoperative GFR value, preoperative contralateral GFR value, β2-microglobulin, tumor size and postoperative eGFR value. (P＜0.05, detailed in Table 1).

Table 1 Comparison of characteristics between CKD group and no-CKD group
characteristics	CKD group（n=189）	no-CKD group（n=311）	P value
	percentage or median (rang)
age (year)	58(33-85)	51(27-85)	0.000
age group			0.000
≤44	17(9.0%)	84(27.0%)
45-59	91(48.1%)	147(47.3%)
60-74	63(33.3%)	70(22.5%)
≥75	18(9.5%)	10(3.2%)
sex			0.002
male	142(75.1%)	192(61.7%)
female	47(24.9%)	119(38.3%)
weight (Kg)	71(42-104)	68(41-101)	0.012
height (cm)	169(149-191)	167(143-190)	0.718
hypertension	64(33.9%)	80(25.7%)	0.052
diabetes	16(8.5%)	28(9.0%)	0.837
smoking history	52(27.5%)		0.470
proteinuria	29(15.3%)	55(17.7%)	0.497
kidney disease	51(27.0%)	90(28.9%)	0.638
anemia	10(5.3%)	20(6.4%)	0.603
total GFR value	75.5(40.3-173.2)	86.2(50.9-134.1)	0.000
contralateral GFR value	36.6(19.7-105.8)	42.4(25.5-66.2)	0.000
BMI（kg/m²）	24.8(16.0-36.8)	24.5(16.4-33.0)	0.080
fat	13(6.9%)	21(6.8%)	0.957
abnormal β2-microglobulin	36(19.0%)	40(12.9%)	0.031
hyperlipidemia	86(45.5%)	122(39.2%)	0.168
tumur size (cm)	4.7(2.0-13.0)	5.0(1.3-19.0)	0.028
T stage			0.223
T1	139(73.5%)	206(66.2%)
T2	23(12.2%)	69(22.2%)
T3	21(11.1%)	33(10.6%)
T4	5(2.6%)	1(0.3%)
unclassified	1(0.5%)	2(0.6%)
Furhman grade			0.509
1	26(13.8%)	55(17.7%)
2	117(61.9%)	144(46.3%)
3	30(15.9%)	70(22.5%)
4	6(3.2%)	11(3.5%)
unclassified	10(5.3%)	31(10.0%)
postoperative eGFR value^a	51.6(25.6-92.4)	65.4(38.9-128.5)	0.000
a. calculated within one week after surgery

Above significant factors were included in logistic multiple regression analysis and showed that age (OR=1.038, 95%CI=1.002-1.076), preoperative contralateral GFR value (OR=0.934, 95%CI=0.884-0.988) and postoperative eGFR value (OR=0.892, 95%CI=0.854-0.931) were independent risk factors. Patients had greater likelihood of CKD with increasing age，lower preoperative contralateral kidney GFR value or postoperative eGFR value.

RN is the classical treatment for localized renal cell carcinoma. Ideally, it should not cause CKD if the contralateral kidney is well preserved since good renal function can be maintained in renal transplant patients. However, opponents proposed that the kidney transplant patients were all well selected and their clinical outcome couldn’t be used to predict the outcome of RN patient, who are usually elder lies with decreased renal function preservation. Some of them have underlying chronic disease which will cause worsening kidney function over time⁵. In addition, pathology examination of radical nephrectomy always shows some kidney disease in the “no-tumor part”⁶, which may be associated with CKD after RN⁷. Therefore, the probability of CKD after radical nephrectomy is often higher than expected.

Previously, Minato⁸ found that the incidence of CKD 3-year after radical nephrectomy was 37%. Jeon⁹ found that 41.7% T1a patients will suffer from CKD after nephrectomy. In our study, it shows that 43.4% patients had CKD postoperatively after a relatively long follow-up. We also found that only 26 patients (13.7%) with normal immediate postoperative (within one week) eGFR would develop CKD within 5 years. Xu¹⁰ also showed that the incidence of CKD was much higher in patients who developed postoperative acute kidney injury than patients who didn’t (18.64% vs. 5.94%), which means acute kidney injury after nephrectomy may be a new nomogram to predict postoperative renal function.

Spontaneous recovery of kidney function was observed in 40 (21.2%) patients who had CKD after RN in our study. We consider that their kidney functions maybe haven’t been damaged seriously by functional compensation worked. Their postoperative eGFR value, as observed, were usually more than 50ml/min/1.73m². In our study, 155 patients were followed up for more than 6 years, among whom, 78 patients didn’t get CKD all the time. Thus, we found that if CKD didn’t happen within 5 years after surgery, it would not happen in following time. And we considered that the kidney function will be compensatory recovery within 5 years after nephrectomy. So the routine check examination for kidney function would not be necessary since the 5th years, possibly avoiding the unnecessary cost on the related items.

Previous studies showed that, age, race, sex, diabetes, hypertension, smoking, obesity, proteinuria and some clinical factors were risk factors for chronic kidney disease^11,12,13,14. In our study, there were significant differences between CKD group and no-CKD group in age, sex, preoperative GFR value, preoperative contralateral GFR value, β2-microglobulin, tumor size and postoperative eGFR value. Multiple regression analysis showed that age, preoperative contralateral GFR value and postoperative eGFR value were independent risk factors of CKD postoperatively.

The preoperative evaluation of kidney function was very important for renal cancer patients. We consider preoperative radionuclide renal imaging was useful for the evaluation of the contralateral kidney function and for the prediction of the risk of acute renal failure after surgery. In our study, approximately 50% of patients developed postoperative CKD if their contralateral GFR value was less than 40ml/min/1.73m². If the contralateral GFR value was less than 30ml/min/1.73m², the incidence increased to nearly 70%.

According to the data of United States Renal Data System¹⁵, about 60% patients with end stage renal disease (ESRD) were older than 75 years old. In our study, both the univariate analysis and the multiple regression analysis showed that age was one of the risk factors of postoperative CKD (P༜0.001). Our stratified analysis showed that the risk of CKD was increased with age. Moreover, there was a high incidence of CKD among patients older than 75 years old. So, the selection of proper surgery plan and preoperative suggestion seemed to be very important for elders. Thus, we conclude that careful patient selection in elderly patient group was very important.

Our univariate analysis showed that “tumor size” was significantly different between CKD group and no-CKD group, However, multiple regression analysis not confirming that “tumor size” was an independent risk factor. Clinically, it was sometimes hard to choose the surgery plan for relatively small volume renal tumor, especially those endogenous or parapelvic tumors. In our study, we analyzed the patients of T1-2N0M0 stage, with the 5-years incidence of CKD for T1a、T1b、T2 stage as 42.6%, 44% and 31.7% respectively, and the P value was 0.036. That is, the incidence of CKD in patients with localized renal cell carcinoma decreases with increased size of tumor. In other words, the incidence of CKD was higher at T1a stage than at T1b stage. Several studies^16,17 also reported a higher risk of postoperative CKD in patients with small size tumors compared with larger tumors. As most renal cell carcinoma was slow growing, we hypotheses was that, the compensation of contralateral kidney was more developed before RN in bigger ipsilateral tumor size, and patients were able to tolerate loss of nephrons during RN better. Recently, Robert¹⁸ found a significant interaction between age and tumor size, that is, tumor size may not have a protective effect on postoperative renal function, but this needs to be confirmed by further studies. Given that tumor size and age play important roles, partial nephrectomy may be a better choice for T1a stage or elder patients in order to decrease the incidence of postoperative CKD. However, it must be weighed against the increase of the perioperative risk especially for elderlies.

Our study showed a significant increased risk of CKD post RN especially for elder patients. The preoperative contralateral GFR value and postoperative eGFR value may be useful in evaluating the risk of developing postoperative CKD in renal cancer patients. And these indicators can be used to assess prognosis of renal function and develop appropriate follow-up plans for post radical nephrectomy patients. So, preoperative renal function assessment and post operative renal function follow up are recommended.

eGFR, estimated glomerular filtration rate; CKD, chronic kidney dysfunction; OR, odds ratio; MDRD, Modification of Diet in Renal Disease; RN, radical nephrectomy; AJCC, American Joint Committee on Cancer; Scr, serum creatinine; K/DOQI, Kidney Disease Outcome Quality Initiative.

Ethics approval and consent to participate:

Ethics approval was obtained from the Ethics Committee of Zhejiang Provincial People’s Hospital. All patients in this study were informed consent to participate this study.All methods in this study were carried out in accordance with relevant guidelines and regulations.

Consent for publication:

All patients related to this study consent to publicate this article.

Availability of data and materials:

All data generated or analysed during this study are included in this published article and available from the corresponding author.

Competing interests:

The authors declare no conflict of interest.

Funding:

This project was funded by Zhejiang Medical and Health Science and Technology Project (Grant No. 2019RC110) and Basic public welfare research program of Zhejiang Province (Grant No. LBQ20H050001).

Authors' contributions:

Shuai Wang and Zhenghong Liu contributed to writing/editing and data collection or management; Dahong Zhang and Fei Xiang contributed to suggestions and data proofreading; Wei Zhang gave approval of the final version of this work. All authors read and approved the final manuscript.

Acknowledgements:

Not applicable.

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The incidence and risk factors of chronic kidney disease after radical nephrectomy in patients with renal cell carcinoma

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Abstract

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1. Background

2. Methods

3. Results

4. Discussion

5. Conclusions

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