Tumor size and postoperative kidney function following radical nephrectomy

Figures & data

Figure 1 Study participants. Flow diagram demonstrating the application of exclusion criteria in study cohorts.

Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; RCC, renal cell carcinoma.

Figure 2 Comparison of (A) pre- and (B) postoperative estimated glomerular filtration rate (eGFR) by patients grouped by age and tumor size/indication. Box and whisker plot of pre- and postoperative eGFR, with patients subgrouped by age and indication. Postoperative kidney function was recorded at approximately 12 months after surgery for the majority of patients.

Table 1 Clinical characteristics of patients grouped by indication/tumor size, and age

	Live kidney donors		Tumors ≤70 mm		Tumors >70 mm
Age (years):	<65	≥65	<65	≥65	<65	≥65
	(N=189)	(N=35)	(N=354)	(N=200)	(N=117)	(N=52)
Age at time of surgery—years
Median [IQR]	52 [46–60]	68 [66–70]	56 [49–60]	70 [67–73]	55 [48–60]	70 [67–73]
Sex
Female	99 (52)	16 (46)	132 (37)	62 (31)	39 (33)	19 (37)
Male	90 (48)	19 (54)	222 (63)	138 (69)	78 (67)	33 (63)
Charlson comorbidity index (score)
0–1	189 (100)	35 (100)	296 (84)	149 (75)	103 (88)	39 (75)
≥2	-	-	58 (16)	51 (25)	14 (12)	13 (25)
Preoperative eGFR—mL/min per 1.73m^2
Median [IQR]	98 [88–105]	80 [72–93]	93 [77–105]	76 [65–86]	86 [71–99]	73 [58–89]
<60	3 (2)	3 (9)	20 (6)	34 (17)	14 (12)	14 (27)
Postoperative eGFR—mL/min per 1.73m^2
Median [IQR]	63 [55–71]	51 [42–58]	60 [49–71]	49 [40–56]	61 [53–72]	52 [43–64]
<60	77 (41)	29 (83)	182 (51)	169 (85)	54 (46)	34 (66)
(45–59)	66 (35)	17 (49)	135 (38)	93 (47)	43 (37)	17 (33)
(<45)	11 (6)	12 (34)	47 (13)	76 (38)	11 (9)	17 (33)
eGFR Decrease—mL/min per 1.73m^2
Median [IQR]	34 [26–41]	29 [22–36]	30 [23–41]	26 [20–34]	22 [12–35]	18 [8–30]
Follow-up time—months
Median [IQR]	12.1 [10.0–13.2]	12.1 [11.1–13.0]	12.0 [10.1–13.6]	11.9 [9.9–13.4]	11.9 [9.9–13.1]	11.5 [7.9–13.2]

Notes: Data presented as count (%), unless otherwise indicated. Postoperative kidney function was recorded at approximately 12 months after surgery for the majority of patients.

Abbreviations: eGFR, estimated glomerular filtration rate.

Table 2 Associations between patient and tumor characteristics, and chronic kidney disease (CKD) upstaging in 944 patients who underwent radical nephrectomy for kidney tumors, considering the interaction between tumor size and patient characteristics

	CKD upstaged
	No N (%)	Yes N (%)	Crude OR (95% CI)	Adjusted OR ^a (95% CI)	Crude RR (95% CI)	Adjusted RR (95% CI)	Interaction P-value ^b
Patient characteristics	(N=371)	(N=573)
Age at diagnosis—years
<65	282 (76)	248 (43)	1		1
≥65	89 (24)	325 (57)	4.2 (3.1–5.6)		1.7 (1.5–1.9)		0.03
Per 5 year increase	-	-	1.5 (1.4–1.6)		1.1 (1.0–1.2)
P-value			<0.001		<0.001
Age at diagnosis (expanded by tumor size) ^c
(Tumor <70mm)
<65	178 (48)	176 (31)	1	1	1	1
≥65	47 (13)	248 (43)	5.3 (3.7–7.7)	5.2 (3.5–7.5)	1.7 (1.5–1.9)	1.7 (1.5–1.9)
(Tumor ≥70mm)
<65	67 (18)	50 (9)	0.8 (0.5–1.2)	0.8 (0.5–1.1)	0.9 (0.7–1.1)	0.9 (0.7–1.1)
≥65	26 (7)	48 (8)	1.9 (1.1–3.1)	1.9 (1.0–3.1)	1.3 (1.1–1.6)	1.3 (1.1–1.6)
Sex
Female	144 (39)	187 (33)	1	1	1	1
Male	227 (61)	386 (67)	1.3 (1.0–1.7)	1.4 (1.0–1.9)	1.1 (1.0–1.2)	1.1 (0.9–1.2)	0.93
P-value			0.05	0.04	0.05	0.07
Charlson comorbidity index
Low-medium (0–1)	312 (84)	437 (76)	1	1	1	1
High (≥2)	59 (16)	136 (24)	1.6 (1.1–2.3)	1.1 (0.7–1.5)	1.2 (1.1–1.3)	1.0 (0.9–1.2)	0.89
P-value			0.004	0.73	0.002	0.38
Preoperative eGFR—mL/min per 1.73m^2
≥80	226 (61)	105 (18)	1	1	1	1
60–79	100 (27)	368 (64)	7.9 (5.8–11.0)	5.9 (4.2–8.4)	2.5 (2.1–2.9)	2.5 (2.1–2.9)	0.54
45–59	45 (12)	100 (17)	4.8 (3.1–7.3)	2.2 (1.4–3.6)	2.2 (1.8–2.6)	2.2 (1.8–2.6)	0.75
P-value			<0.001	<0.001	<0.001	<0.001
Tumor characteristics
Tumor histology
Clear cell	271 (73)	416 (73)	1	1	1	1
Other	100 (27)	157 (27)	1.0 (0.8–1.4)	1.0 (0.7–1.4)	1.0 (0.9–1.1)	1.0 (0.9–1.1)
P-value			0.88	0.83	0.88	0.83
Tumor crossed polar lines
No	219 (59)	346 (60)	1	1	1	1
Yes	119 (32)	186 (32)	0.9 (0.7–1.3)	1.0 (0.7–1.3)	1.0 (0.9–1.1)	1.0 (0.9–1.1)
P-value			0.94	0.96	0.94	0.99
Tumor maximum diameter—mm
≤70	225 (61)	424 (74)	1	1	1	1
>70	93 (25)	98 (17)	0.6 (0.4–0.8)	0.6 (0.4–0.8)	0.8 (0.7–0.9)	0.8 (0.7–0.9)
Missing	53 (14)	51 (9)
P-value			<0.001	0.004	0.002	0.002

Notes: Crude and adjustedOR, risk ratio (RR) estimated using logistic regression or log-binomial regression, respectively. ^aEstimates adjusted for confounders only, not potential mediators. Adjustment variables: sex – age; body mass index (BMI) – age, sex, socioeconomic status (SES); Charlson comorbidity index – age, sex, SES; preoperative estimated glomerular filtration rate (eGFR) – age, sex, Charlson comorbidity index, SES; histology – age, sex, BMI, Charlson comorbidity index, smoker status, preoperative eGFR; location relative to polar lines – tumor histology; Tumor maximum diameter – age, Charlson comorbidity index, tumor histology. ^bP-value for first-order interaction term between tumor size and each exposure in logistic regression analysis. ^cAdjustment for sex, and Charlson comorbidity index. Percentages do not add up to 100% due to missing data on tumor size for some patients. Postoperative kidney function was recorded at approximately 12 months after surgery for the majority of patients.

Abbreviation: CKD, chronic kidney disease.

Figure 3 Forest plot showing odds of chronic kidney disease upstaging in patients grouped by tumor size/indication. (A) Forest plot showing associations between patients grouped by indication/tumor size and age, with adjustment made only for potential confounders (sex and Charlson comorbidity index). (B) The same model as (A), with adjustment also made for preoperative estimated glomerular filtration rate (eGFR). The estimates remain relatively similar for all groups, except large tumors, where the effect size reverses following adjustment for eGFR. Postoperative kidney function was recorded at approximately 12 months after surgery for the majority of patients.

Table 3 Comparisons of postoperative kidney function between donor and tumor nephrectomy, grouped by age and tumor size

Linear regression analysis evaluating associations between groups and postoperative eGFR
Indication	Age	N	Crude β (95% CI)	P-value	Adjusted β (95% CI) ^a	P-value	Adjusted β (95% CI) ^b	P-value
Donor	<65	189	Ref.		Ref.		Ref.
≥65	35	−13.0 (−16.0, −9.4)	<0.001	−13.0 (−16.0, −9.3)	<0.001	−5.7 (−8.9, −2.4)	0.001
Tumor <70 mm	<65	354	−2.2 (−4.8, 0.4)	0.09	−0.5 (−3.2, 2.2)	0.72	1.5 (−0.7, 3.8)	0.19
≥65	200	−15.0 (−17.0, −12.0)	<0.001	−12.0 (−15.0, −9.4)	<0.001	−3.0 (−5.7, −0.3)	0.03
Tumor ≥70 mm	<65	117	0.2 (−3.4, 3.7)	0.92	1.8 (−1.8, 5.4)	0.33	7.0 (3.7, 10.0)	<0.001
	≥65	52	−7.7 (−13.0, −2.5)	0.004	−5.7 (−11.0, −0.3)	0.04	4.5 (−0.2, 9.3)	0.06
Logistic regression analysis evaluating associations between groups and CKD upstaging
Indication	Age	N	Crude OR (95% CI)	P-value	Adjusted OR (95% CI) ^a	P-value	Adjusted OR (95% CI) ^b	P-value
Donor	<65	189	1		1		1
≥65	35	6.2 (2.5–15.0)	<0.001	6.2 (2.5–15.0)	<0.001	3.5 (1.5–8.1)	0.005
Tumor <70 mm	<65	354	1.5 (1.1–2.2)	0.02	1.4 (0.9–2.0)	0.10	1.1 (0.8–1.7)	0.53
≥65	200	7.1 (4.4–11.0)	<0.001	6.1 (3.7–10.0)	<0.001	2.7 (1.6–4.6)	<0.001
Tumor ≥70mm	<65	117	1.2 (0.7–1.9)	0.53	1.0 (0.6–1.7)	0.88	0.6 (0.3–0.9)	0.05
	≥65	52	2.1 (1.1–3.9)	0.02	1.9 (1.0–3.5)	0.05	0.7 (0.3–1.4)	0.26
Log-binomial regression analysis evaluating associations between groups and CKD upstaging
Indication	Age	N	Crude RR (95% CI)	P-value	Adjusted RR (95% CI) ^a	P-value	Adjusted RR (95% CI) ^b	P-value
Donor	<65	189	1		1		1
≥65	35	2.0 (1.6–2.6)	<0.001	2.0 (1.6–2.6)	<0.001	1.4 (1.1–1.8)	0.006
Tumor <70mm	<65	354	1.3 (1.0–1.6)	0.02	1.2 (0.9–1.5)	0.07	1.2 (0.9–1.4)	0.16
≥65	200	2.1 (1.7–2.5)	<0.001	2.0 (1.6–2.4)	<0.001	1.5 (1.2–1.8)	<0.001
Tumor ≥70mm	<65	117	1.1 (0.8–1.4)	0.53	1.1 (0.8–1.4)	0.71	0.9 (0.7–1.2)	0.50
≥65	52	1.4 (1.1–1.9)	0.01	1.4 (1.0–1.9)	0.02	1.1 (0.8–1.5)	0.45

Notes: ^aAdjustment made for sex, and Charlson comorbidity index. ^bAdjustment made for preoperative estimated glomerular filtration rate (eGFR), sex, and Charlson comorbidity index. Postoperative kidney function was recorded at approximately 12 months after surgery for the majority of patients.

Abbreviations: CKD, chronic kidney disease; RR, relative risk.

Figure 4 Potential role of collider-stratification bias. This directed acyclic graph (DAG) depicts the hypothesized causal relationship between preoperative estimated glomerular filtration rate (eGFR) and postoperative eGFR, confounded by both tumor size and other risk factors for chronic kidney disease (CKD). In this model, the relationship between tumor size and postoperative eGFR is shown to be mediated by preoperative eGFR, as larger tumors tend to cause preoperative reductions in kidney function. Physiologically, it would be expected that the direct effect of tumor size on postoperative eGFR is quite small in magnitude, because once a tumor has been excised, it should not continue to influence kidney function. Also depicted in this model are other risk factors for CKD, most of which were unmeasured, which would cause reductions in both pre- and postoperative eGFR. Unlike tumor size, other risk factors for CKD will probably lead to ongoing deterioration in kidney function. Therefore, preoperative eGFR becomes a collider in this DAG. When evaluating the association between tumor size and postoperative eGFR, adjusting for this collider may result in a biased estimate, because a spurious causal pathway is opened (Tumor Size → Preoperative eGFR ← CKD Risk Factors → Postoperative eGFR). This becomes a problem because an artificial comparison is generated. The existence of a low preoperative eGFR can be caused by a large tumor, CKD risk factors, or both; however, if a patient has a low preoperative eGFR caused by a growing tumor, it becomes less likely that the preoperative eGFR is caused by CKD risk factors. This is not taken into account by the model, which assumes a low preoperative eGFR has the same likelihood of causing low postoperative eGFR, regardless of the underlying reason (because the CKD risk factors are largely unmeasured, and not accounted for in the model). Consequently, patients with low preoperative eGFR caused by something that is unlikely to be associated with ongoing functional deterioration (a large tumor) are compared with patients who have a low preoperative eGFR caused by something that is likely to be associated with ongoing functional deterioration (CKD risk factors). This results in larger tumors being inappropriately seen as protective.

Table S1 Clinical characteristics of nephrectomy patients grouped by indication

		Radical nephrectomy	Donor nephrectomy	Excluded ^b	Excluded ^c
		(N=815)	(N=224)	(N=629)	(N=229)
Age at diagnosis—years
	Median (IQR)	60 (53–68)	55 (48–62)	68 (57–77)	71 (62–78)
	<65	530 (56)	185 (84)	262 (42)	74 (32)
	65–75	285 (30)	35 (16)	153 (24)	74 (32)
	>75	-	-	214 (34)	81 (34)
Sex
	Female	282 (35)	115 (51)	227 (36)	73 (32)
	Male	533 (65)	109 (49)	402 (64)	156 (68)
Charlson comorbidity index (score)
	Low (0)	490 (60)	224 (100) ^a	347 (55)	110 (48)
	Medium (1)	179 (22)	-	127 (20)	56 (24)
	High (≥2)	146 (18)	-	155 (25)	63 (28)
Preoperative eGFR—mL/min per 1.73 m^2
	Median (IQR)	83 (70–98)	96 (83–104)	64 (44–84)	60 (41–86)
	≥80	451 (55)	181 (81)	107 (17)	46 (20)
	60–79	263 (32)	37 (17)	89 (14)	32 (14)
	<59	101 (15)	6 (3)	161 (26)	77 (34)
	Missing	-	-	272 (43)	74 (32)
Tumor diameter—mm
	Median (IQR)	48 (36–69)	-	47 (35–67)	42 (29–70)
	<40	213 (26)	-	180 (29)	48 (21)
	40–70	341 (42)	-	230 (37)	40 (17)
	>70	169 (20)	-	106 (17)	27 (12)
	Missing	92 (11)	-	113 (18)	114 (50)
TNM staging
	T1	449 (55)	-	339 (54)	83 (36)
	T2	85 (10)	-	66 (11)	27 (12)
	T3/4	281 (34)	-	222 (35)	72 (31)
	N1	59 (7)	-	39 (6)	65 (28)
	M1	75 (9)	-	48 (8)	140 (61)

Notes: Data presented as count (%) unless otherwise indicated. ^aDonors were assigned a Charlson comorbidity score of zero.^b Patients who underwent radical nephrectomy but who were excluded from main analysis. ^cPatients who had kidney cancer but did not undergo surgery

Abbreviation: eGFR, estimated glomerular filtration rate.

Table S2 Application of exclusion criteria between patients grouped by age and tumor size in 1,981 patients diagnosed with RCC^a

	Tumors ≤70 mm		Tumors >70 mm
Age (years):	<65	≥65	<65	≥65
Exclusion criteria	(N=949)	(N=722)	(N=180)	(N=130)
Nonsurgical management	19 (2)	69 (10)	13 (7)	14 (11)
Abnormal contralateral kidney	3 (<1)	2 (<1)	2 (1)	1 (<1)
Missing preoperative eGFR	87 (9)	85 (12)	29 (16)	15 (12)
Missing postoperative eGFR	54 (6)	29 (4)	10 (6)	7 (5)
Partial nephrectomy	414 (44)	210 (29)	6 (3)	3 (2)
Preoperative eGFR <45	18 (2)	32 (4)	3 (<1)	16 (12)
Age >75 years	0 (0)	95 (13)	0 (0)	22 (17)
Excluded	595 (63)	522 (72)	63 (72)	78 (60)
Included	354 (37)	200 (28)	117 (28)	52 (40)

Note: ^aData presented as count (%), unless otherwise indicated.

Abbreviations: eGFR, estimated glomerular filtration rate (in mL/min per 1.73m²); RCC, renal cell carcinoma.

Table S3 Association between tumor size and postoperative kidney function, stratified by age

Tumor size	aOR (95% CI)	β (95% CI)	RR (95% CI)
Age <65-years
<70mm	1	Ref.	1
≥70mm	0.8 (0.5–1.1)	2.3 (−1.1, 5.7)	0.9 (0.7–1.1)
P-value	0.2	0.2	0.2
Age ≥65-years
<70mm	1	Ref.	1
≥70mm	0.4 (0.2–0.6)	5.2 (1.6–8.9)	0.8 (0.6–0.9)
P-value	<0.001	0.005	0.004

Notes: Postoperative kidney function was recorded at approximately 12 months after surgery for the majority of patients. Adjustment made for age, Charlson comorbidity index, and tumor histology.

Abbreviations: RR, risk ratio; aOR, adjusted odds ratio; β, linear regression coefficient.

Table S4 Comparisons of postoperative kidney function patients grouped by age and tumor size with narrowed exclusion criteria

Linear regression analysis evaluating associations between groups and postoperative eGFR in patients with preoperative eGFR >30 mL/min per 1.73 m^2
Indication	Age	N	Crude β (95% CI)	P-value	Adjusted β (95% CI) ^a	P-value	Adjusted β (95% CI) ^b	P-value
Tumor <70 mm	<65	360	Ref.		Ref.		Ref.
≥65	221	−14.0 (−16.0, −11.0)	<0.001	−13.0 (−15.0, −10.0)	<0.001	−4.1 (−6.4, −1.7)	<0.001
Tumor ≥70 mm	<65	118	2.3 (−1.1, 5.7)	0.18	2.0 (−1.3, 5.5)	0.22	5.3 (2.6, 8.1)	<0.001
	≥65	64	−9.4 (−14.0, −5.0)	<0.001	−8.7 (−13.0, −4.4)	<0.001	2.3 (−1.4, 6.0)	0.21
Linear regression analysis evaluating associations between groups and postoperative eGFR in patients with any preoperative eGFR value
Tumor <70 mm	<65	372	Ref.		Ref.		Ref.
≥65	232	−14.0 (−17.0, −11.0)	<0.001	−12.0 (−15.0, −9.4)	<0.001	−3.2 (−5.5, −0.9)	0.005
Tumor ≥70 mm	<65	120	3.0 (−0.6, 6.8)	0.10	2.3 (−1.0, 6.2)	0.16	5.6 (2.9, 8.3)	<0.001
≥65	67	−8.5 (−13.0, −3.8)	<0.001	−8.0 (−12.0, −3.1)	<0.001	3.6 (0.06, 7.2)	0.05

Notes: ^aAdjustment made for sex, and Charlson comorbidity index. ^bAdjustment made for preoperative estimated glomerular filtration rate (eGFR), sex, and Charlson comorbidity index. Postoperative kidney function was recorded at approximately 12 months after surgery for the majority of patients.

Abbreviation: β, linear regression coefficient; eGFR, estimated glomerular filtration rate.

Table S5 Direct, indirect and total effects of various exposures on pre- and postoperative eGFR

Analysis performed assuming a direct causal path between tumor size and postoperative eGFR
	Direct effects	Indirect effects	Total effects
	β (95% CI)	β (95% CI)	β (95% CI)
Preoperative eGFR
Charlson comorbidity index	−0.5 (−2.1, 1.0)	-	−0.5 (−2.1, 1.0)
Age (years)	−0.9 (−1.0, −0.8)	0.0 (−0.1, 0.1) ^a	−0.9 (−1.0, −0.8)
Tumor Ssize (cm)	−1.0 (−1.4, −0.6)	-	−1.0 (−1.4, −0.6)
Postoperative eGFR
Charlson comorbidity index	−1.7 (−2.9, −0.5)	−0.2 (−1.0, 0.5) ^b	−1.9 (−3.4, −0.5)
Age (years)	−0.2 (−0.3, −0.1)	−0.4 (−0.5, −0.4) ^c	−0.7 (−0.8, −0.6)
Tumor size (cm)	1.0 (0.6, 1.3)	−0.5 (−0.7, −0.3) ^d	0.5 (0.1, 0.9)
Preoperative eGFR	0.5 (0.4, 0.5)	-	0.5 (0.4, 0.5)
Analysis performed assuming no direct causal path between tumor size and postoperative eGFR
	Direct effects	Indirect effects	Total effects
	β (95% CI)	β (95% CI)	β (95% CI)
Preoperative eGFR
Charlson comorbidity index	−0.4 (−1.8, 1.0)	-	−0.4 (−1.8, 1.0)
Age (years)	−0.9 (−1.0, −0.6)	0.0 (−0.1, 0.1) ^a	−0.9 (−1.3, −0.6)
Tumor size (cm)	−0.9 (−1.3, −0.6)	-	−0.9 (−1.3, −0.6)
Postoperative eGFR
Charlson comorbidity index	−1.7 (−2.8, −0.6)	−0.2 (−0.8, 0.5) ^b	−1.9 (−3.2, −0.6)
Age (years)	−0.2 (−0.4, −0.2)	−0.4 (−0.5, −0.3) ^c	−0.7 (−0.8, −0.6)
Tumor size (cm)	-	−0.4 (−0.6, −0.2) ^d	−0.4 (−0.6, −0.2)
Preoperative eGFR	0.4 (0.4, 0.5)	-	0.4 (0.4, 0.5)

Notes: ^aIndirect effects of age through Charlson comorbidity index. ^bIndirect effects of Charlson comorbidity index through preoperative eGFR. ^cIndirect effects of age through Charlson comorbidity index and preoperative eGFR. ^d Indirect effects of tumor size through preoperative eGFR. Postoperative kidney function was recorded at approximately 12 months after surgery for the majority of patients.

Abbreviations: β, linear regression coefficient; eGFR, estimated glomerular filtration rate (in units of mL/min per 1.73m²)

Figure S1 Structural models with and without a direct causal pathway between tumor size and postoperative estimated glomerular filtration rate (eGFR). (A) Structural equation model evaluating the relative contributions of the most significant patient and tumor characteristics on postoperative eGFR; this model assumes there is a direct causal effect of tumor size on postoperative eGFR. The net total effect of tumor size on postoperative eGFR is positive (β: 0.5, 95% CI: 0.4, 0.5). (B) The same model as A, except there is no direct causal association between tumor size and postoperative eGFR. The net total effect of tumor size on postoperative eGFR reverses direction (β: −0.4, 95% CI: −0.6, −0.2).