International Journal of Urology (2019) doi: 10.1111/iju.

14079

Original Article

On-clamp versus off-clamp partial nephrectomy: Propensity score-

matched comparison of long-term functional outcomes
Giuseppe Simone,1 Umberto Capitanio,2 Gabriele Tuderti,1 Fabrizio Presicce,3 Costantino Leonardo,3
Mariaconsiglia Ferriero,1 Leonardo Misuraca,1 Manuela Costantini,1 Alessandro Larcher,2 Francesco
Minisola,1 Salvatore Guaglianone,1 Umberto Anceschi,1 Fabio Muttin,2 Alessandro Nini,2 Francesco
Trevisani,2 Francesco Montorsi,2 Roberto Bertini2 and Michele Gallucci1,3
1
Department of Urology, “Regina Elena” National Cancer Institute, Rome, 2Department of Urology, Hospital San Raffaele,
University Vita Salute, Milan, and 3Department of Urology, Sapienza University, Rome, Italy

Abbreviations & Acronyms
ASA = American Society of
Anesthesiologists
CT = computed tomography
eGFR = estimated
glomerular filtration rate
HR = hazard ratio
MDRD = Modification of
Diet in Renal Disease
Off-C = off-clamp
On-C = on-clamp
PN = partial nephrectomy
PSM = propensity score
matching
RCC = renal cell carcinoma
RF = renal function
WI = warm ischemia
WIT = warm ischemia time
WMD = weighted mean
difference
Correspondence: Giuseppe
Simone Ph.D., F.E.B.U.,
Department of Urology, “Regina
Elena” National Cancer Institute,
Via Elio, Chianesi 53, 00144
Rome, Italy. Email:
puldet@gmail.com
Received 5 March 2019;
accepted 1 July 2019.
Objectives: To compare long-term functional outcomes of off-clamp or on-clamp
partial nephrectomy patients of two high-volume centers with cT1–2/N0 M0 renal tumors
and baseline estimated glomerular filtration rate >60 mL/min.
Methods: A 3:1 propensity score-matched analysis was used to select two
homogeneous cohorts to compare off-clamp versus on-clamp partial nephrectomy.
Joinpoint regression analysis was used to compare the 2–8-year probabilities of
estimated glomerular filtration rate modifications in both selected cohorts. The Kaplan–
Meier method assessed the risk of developing a stage ≥3b chronic kidney disease during
follow up. Multivariable analyses aimed to identify predictors of renal function
deterioration. Perioperative complications and oncological outcomes were compared.
Results: Overall, 1073 patients were included (588 on-clamp and 485 off-clamp). After
applying the propensity score-matched analysis, the two cohorts of 157 on-clamp and 472
off-clamp patients did not differ for all covariates, except for warm ischemia time and last
estimated glomerular filtration rate. At joinpoint analysis, the off-clamp group showed
higher probabilities of maintaining an unmodified estimated glomerular filtration rate
(P = 0.02). The probability of developing a stage ≥3b chronic kidney disease was
significantly higher (P < 0.001) in the on-clamp cohort. At multivariable analysis, estimated
glomerular filtration rate at discharge and off-clamp approach were independent predictors
of improved functional outcomes. Perioperative complications were comparable among
the two cohorts (P = 0.67). There were not any statistically significant differences in terms
of cancer-specific survival (P = 0.26) and overall survival (P = 0.18).
Conclusions: Off-clamp partial nephrectomy seems to offer a higher probability of
maintaining 100% estimated glomerular filtration rate after surgery. In our cohort,
patients undergoing on-clamp partial nephrectomy presented a 7.3-fold increased risk of
developing a severe chronic kidney disease during follow up.
Key words: functional outcomes, off-clamp, on-clamp, partial nephrectomy, propensity
score matching.
Introduction
RCC represents 2–3% of all malignancies, with an incidence of 5.8/100 000.1,2 In the past
decades, the improvements in preoperative staging and surgical procedures have made PN the
standard treatment over radical nephrectomy for localized RCC, whenever technically feasi-
ble.2 PN has shown equivalent oncological outcomes and a superior RF preservation, with a
consequent expected reduction of cardiovascular morbidity.3,4 Thus, the number of PN proce-
dures has significantly increased over time,5 with the consequent demand for continuous
improvements of the procedure.5,6
An ideal PN includes: negative surgical margins, no postoperative complications and mini-
mal RF impairment.7 Thus, to provide a bloodless surgical field that facilitates an accurate
tumor resection and a precise closure of the renal defect, transient hilar clamping is normally
required.7 In contrast, the transitory interruption of renal blood flow inevitably results in a
renal WI, undermining the goal of RF preservation.8–10

© 2019 The Japanese Urological Association 1

G SIMONE ET AL.
The real role of WI on RF is still controversial, as recent
studies recommended 25 min as the safety threshold of WIT
during PN, and showed that every minute of hilar clamping
has a detrimental effect on RF.8–11 Therefore, the use of Off-
C procedures has been increasingly proposed to maximize the
RF preservation. However, a definitive functional benefit of
Off-C PN has not yet been proved.12 A possible protective
effect on postoperative RF could be counterbalanced by more
complications and a greater positive surgical margin rate, as a
result of higher bleeding and subsequent suboptimal vision.12
Several studies comparing Off-C PN with conventional
On-C PN have already been published with conflicting
results.13,14 Probably small sample size, heterogeneous cohort
of enrolled patients and short-term monitoring of the RF
hamper the correct assessment in most of these studies.13,14
Therefore, many controversies remain on this topic, contin-
uing to be a relevant area of investigation.
The aim of the present study was to compare long-term
(up to 8 years) renal functional outcomes after either Off-C
PN or On-C PN in patients with cT1–2/N0 M0 renal tumors
and baseline eGFR >60 mL/min.
Methods
Data were prospectively collected into institutional review board-
approved renal cancer databases of two high-volume centers,
queried for patients who underwent elective PN for unilateral
RCC (cT1–2/N0/M0 tumors) and baseline eGFR >60 mL/min,
between 2003 and 2013. Patients who underwent imperative PN
for bilateral or multiple RCC, as well as those with baseline
eGFR <60 mL/min, were excluded. Overall, 1073 patients met
the inclusion criteria, 485 Off-C and 588 On-C, respectively. The
choice to clamp or not was made at the surgeon’s discretion, with
Off-C PN utilized at rates of 45% (485/1073). No cold ischemia
and/or selective clamping were used in the cohort of patients who
underwent On-C PN (Milan), where main artery clamping was
used. Off-C surgical technique was recently described, and carried
out in the other center involved in the study (Rome).15
Baseline demographic characteristics (sex, age at surgery),
smoking status, personal history of hypertension and/or
type 2 diabetes mellitus, ASA score, surgical margin status,
and WIT (for the On-C PN subgroup only) were prospec-
tively recorded.
Postoperatively, abdominal ultrasonography and chest X-
ray or CT scans were carried out at 6-month intervals for the
first 2 years, then thorax and abdomen CT scans yearly.
RF was assessed at baseline using creatinine value and the
eGFR, calculated with the MDRD equation.16 Progression to
CKD was defined as a sustained decrease in eGFR of ≥25%
within 12 months. In addition patients were classified as
grade (G)1–G5 stages of the CKD classification, based on the
eGFR.17 Patients with moderate-to-severe reduction of RF
(eGFR <45 mL/min) were categorized in stage ≥3b CKD.17
Statistical analysis
A 3:1 PSM analysis was used to minimize the selection bias
of non-random assignment of patients to Off-C PN, as
opposed to On-C PN.
2 © 2019 The Japanese Urological Association
The analysis was carried out with the type of surgery (Off-C
PN vs On-C PN) as the dependent variable; age, sex, tumor size,
ASA score, diabetes/hypertension presence, smoking status,
surgical margins status, baseline eGFR, eGFR at discharge and
follow-up months were the independent variables. This allowed
the investigators to account for differences in covariates
between the groups. Continuous and discrete variables were
reported as the mean  SD and proportions. These were com-
pared with Student’s t-test and the v2-test, respectively.
Joinpoint regression analysis was used to plot the 2–8 year
probabilities of experiencing eGFR decreases of 0%, <25%
and >25% in both PSM cohorts, and therefore to compare the
trends for each of these three subgroups. In addition, Stu-
dent’s t-test was used to compare the mean ages of the two
selected cohorts at different follow-up length.
The Kaplan–Meier method was used to compare the risk of
developing a stage ≥3b CKD (eGFR <5 mL/min) during fol-
low up in the PSM cohorts. Univariable and multivariable Cox
regression analyses were carried out to identify independent pre-
dictors of developing a stage ≥3b CKD during follow up.
Perioperative complications and oncological outcomes of
the selected cohorts were compared with the v2-test and
Kaplan–Meier method, respectively.
All tests were two-sided, and statistical significance was
defined as P < 0.05. Statistical analysis was carried out using
the Statistical Package for the Social Sciences (SPSS v.21;
IBM Corporation, Armonk, NY, USA), as well as the R sta-
tistical software (v.2.14.2; https://cran.r-project.org/).
Results
Demographic, clinical and pathological characteristics of the
enrolled patients are summarized in Table 1. In the whole
cohort, On-C PN patients were significantly younger
(P = 0.001), less frequently smokers (P = 0.01), with a lower
incidence of diabetes (P = 0.001) and hypertension
(P = 0.001), lower ASA scores (P < 0.001), higher baseline
eGFR values (P = 0.003), smaller tumor sizes (P < 0.001),
longer WIT (17 vs 0 min, P < 0.001), higher incidence of
positive surgical margins (P = 0.021), and longer follow up
(P < 0.001). After applying the PSM analysis, the two
cohorts of 157 On-C and 472 Off-C PN patients did not dif-
fer for all demographic, clinical and pathologic covariates
(Table 1; all P ≥ 0.08), except for mean WIT (P < 0.001).
At joinpoint regression analysis, the Off-C PN group
showed significantly higher probabilities of maintaining
unmodified eGFR after surgery after 8 years from surgery
(58% vs 4%, P = 0.02), and significantly lower probabilities
of experiencing eGFR decrease >25% in the first 8 years of
follow up (9% vs 47%, P = 0.02) when compared with
patients undergoing On-C PN (Fig. 1a,b). Furthermore, there
were not any statistically significant differences in terms of
mean age among the two selected cohorts at 24-, 48-, 72-
and 96-month follow up.
The probability of developing a stage ≥3b CKD
(eGFR <45 mL/min) was significantly higher (log–rank
P < 0.001) in the On-C PN cohort (2-, 5- and 8-year risk
0.6%, 4.9% and 15.5% vs 0.8%, 0.8% and 0.8%) when com-
pared with the Off-C PN cohort, respectively (Fig. 2).
 Off-C PN offers better RF outcomes

At multivariable Cox regression analysis, eGFR at dis- CKD was reduced by 6% (HR 0.94, 95% CI 0.91–0.98;
charge and Off-C approach were independent predictors of P = 0.002), whereas the On-C approach was associated with
better renal functional outcomes. For each increasing mL/min a 7.3-fold increased risk of developing a stage ≥3b CKD
of eGFR at discharge, the risk of developing a stage ≥3b (HR 7.33, 95% CI 1.8–29.4; P = 0.005; Table 2).

Table 1 Baseline demographic and clinical data of patients

Whole cohort 1:3 PS matched cohort

On-C PN (n = 588) Off-C PN (n = 485) P-value† On-C PN (n = 157) Off-C PN (n = 472) P-value†
Mean age, years (SD) 57.1  12.4 59.2  12.6 0.001 60.69  11.8 59.7  12 0.3
Male sex, n (%) 420 (71.4) 333 (68.7) 0.324 116 (73.9) 326 (69.1) 0.25
Mean baseline eGFR, mL/min (SD) 89.5  16.1 86.4  17.7 0.003 86.8  15.6 85.9  17.2 0.56
Mean tumor size, cm (SD) 3.41  1.5 3.98  2.4 <0.001 3.46  2 3.77  1.4 0.08
Diabetes, n (%) 44 (7.5) 67 (13.8) 0.001 13 (8.3) 60 (12.7) 0.13
Hypertension, n (%) 226 (38.4) 236 (48.7) 0.001 71 (45.2) 235 (49.8) 0.32
Smoking status, n (%) 113 (19.2) 125 (25.8) 0.01 32 (20.4) 125 (26.5) 0.13
ASA score, n (%) 1 174 (29.6) 1 5 (10.3) <0.001 21 (13.4) 38 (8.1) 0.15
2 334 (56.8) 2 323 (66.6) 107 (68.2) 322 (68.4)
3 78 (13.3) 3 110 (22.7) 28 (17.8) 109 (23.1)
4 2 (0.3) 4 2 (0.4) 1 (0.6) 2 (0.4)
Positive surgical margins, n (%) 22 (3.7) 7 (1.4) 0.021 4 (2.5) 7 (1.5) 0.38
Mean WIT, min (SD) 17 (6.3) 0 <0.001 16.3 (5) 0 <0.001
Mean follow up, months (SD) 69.6 (50) 45.3 (32.2) <0.001 50.2 (32) 49.2 (31) 0.72
Mean eGFR at discharge, mL/min (SD) 79.4 76.9 0.089 77.7  21 78  20 0.84
Mean eGFR at last follow up, mL/min (SD) 69.9 (25.3) 79.5 (17.8) <0.001 73.2 (19.9) 79.2 (17.3) <0.001

Significant variables (P < 0.05) are in bold. †Student’s t-test for continuous variables, and v2-test for categorical variables.

Δ-eGFR100% On-C
(a)
Δ-eGFR100% Off-C (b)
60
50 100
P = 0.02 90 Δ-eGFR<75%
40
80
30 Δ-eGFR≥75%
70
20 60 Δ-eGFR 100%
10 50
0 40
2 4 6 8 30
20
Δ-eGFR≥75% On-C 10
Δ-eGFR≥750% Off-C 0
60 2 3 4 5 6 7 8 2 3 4 5 6 7 8
P = 0.37
50 On-C Off-C
40
30 (c)
20
2 4 6 8 On-C PN (157) Off-C PN (472) p value*
Δ-eGFR<75% On-C
24-mo Mean age (±SD) 59.95 ± 12.03 59.95 ± 11.25 0.81
Δ-eGFR<750% Off-C
50 48-mo Mean age (±SD) 60.1 ± 11.1 60.3 ± 10.7 0.91

40 72-mo Mean age (±SD) 60.6 ± 10.74 61.45 ± 9.02 0.72

P = 0.02
30 96-mo Mean age (±SD) 59.3 ± 11.03 64 ± 8.45 0.23

20
10
0
2 4 6 8

Fig. 1 (a) Subgroup joinpoint regression analysis to plot the 2–8-year probabilities of experiencing eGFR modification in both PSM cohorts. (b) Percentage eGFR
decrease along the 8-year follow up. (c) Mean age comparison of PSM cohorts at 2–8 years follow up.

© 2019 The Japanese Urological Association 3

G SIMONE ET AL.

The overall perioperative complications were comparable 94.9% and 90.9% vs Off-C 99%, 98.5% and 98.5%, respec-
among the two cohorts (On-C 27.4% vs Off-C 22.2%; tively; P = 0.18; Fig. 3a,b).
P = 0.67; Table 3).
Regarding oncological outcomes, there were not any statis-
tically significant differences in terms of cancer-specific sur-
Discussion
vival (2-, 5- and 8-year rate: On-C 100%, 100% and 100% According to the European Association of Urology and
vs Off-C 99.7%, 98.8% and 99.8%, respectively; P = 0.26) American Urological Association guidelines, PN is the
and overall survival (2-, 5- and 8-year rate: On-C 99.2%, referred treatment for cT1 renal tumors, and a practicable

0.40 Follow-up (months) 24 60 96

On-Clamp PN
–Probabilities ± SE 0.6 ± 0.6 4.9 ± 2.2 15.5 ± 5.6
0.35
–N at risk (events) 123 (1) 55 (5) 16 (9)
Off-Clamp PN
Risk of developing eGFR < 45 mL/min

0.30
–Probabilities ± SE 0.8 ± 0.4 0.8 ± 0.4 0.8 ± 0.4
–N at risk (events) 370 (3) 172 (3) 38 (3)
0.25
Log rank P < 0.001

0.20

0.15 Surgical technique

On-clamp
0.10 Off-clamp

0.05

0.00

Fig. 2 Kaplan–Meier analysis comparing the risk

.00 12.00 24.00 36.00 48.00 60.00 72.00 84.00 96.00 108.00 120.00
of developing a stage ≥3b CKD (eGFR <45 mL/
Follow-up length (months) min) during follow up in the PSM cohorts.

Table 2 Univariable and multivariable cox regression analyses to identify predictors of stage 3b CKD development after surgery

Univariable analysis Multivariable analysis

95% CI 95% CI

P-value HR Lower Higher P-value HR Lower Higher

Age <0.001 1.12 1.05 1.18 0.053 1.08 0.99 1.18

Male sex 0.380 1.65 0.54 5.01 – – – –
Baseline eGFR 0.010 0.95 0.91 0.98 0.449 0.98 0.92 1.03
Tumor size 0.810 0.97 0.77 1.23 – – – –
Diabetes 0.027 3.21 1.14 9.04 0.09 3.06 0.81 11.6
Hypertension 0.983 0.99 0.39 2.53 – – – –
Smoking 0.928 0.97 0.51 1.83 – – – –
ASA score 0.99 – – – –
2 vs 1 0.9 1.14 0.14 9.04
3 vs 1 0.96 1.43 0.08 10.47
4 vs 1 0.98 1.58 0.09 13.1
Positive surgical margins 0.726 3.12 0.32 9.25 – – – –
Recurrence 0.399 1.37 0.66 2.880 – – – –
eGFR at discharge <0.001 0.95 0.93 0.975 0.002 0.94 0.91 0.98
On-C vs Off-C 0.036 4 1.09 14.64 0.005 7.33 1.82 29.4

Significant variables (P < 0.05) are in bold.

4 © 2019 The Japanese Urological Association

 Off-C PN offers better RF outcomes

option for cT1b/T2 lesions “when technically feasible.”2,6
Theoretically, clamping during minimally invasive PN pro-
vides a virtually bloodless resection and a proper control of
surgical margins; subsequently, a meticulous renorrhaphy,
although exposing the renal parenchyma to ischemic injury,
is a key step of almost any PN.6
A lower incidence of postoperative acute kidney injury and
CKD after Off-C PN in solitary kidney models has suggested
the use of this approach, even in the elective setting, for
patients with solitary tumor and normal contralateral kid-
ney.11,18
Whereas Off-C approaches have been considered as pri-
mary options in patients with impaired baseline RF, the bene-
fit of Off-C techniques on long-term RF outcomes in patients
with normal baseline RF is yet to be determined.12 Several
retrospective studies have already been published with very
conflicting results.12–14 In 2014, two meta-analyses provided
comparable outcomes.13,14 Trehan included 14 studies, report-
ing better RF outcomes in favor of Off-C PN, with no differ-
ence in peri- and postoperative parameters, surgical
Table 3 Perioperative complications of the PSM selected cohorts
On-C PN
(n = 157)
Clavien grade complications,
n (%)
0 114 (72.6)
1 16 (10.2)
2 21 (13.4)
3 6 (3.8)
4 0 (0)
†v2-test for categorical variables.
complications, and oncological outcomes.13 In detail, the Off-
C technique was associated with a significantly lower reduc-
tion in eGFR than On-C PN (WMD 0.27, 95% CI 0.14–0.40,
P < 0.0001).13 Similarly, 10 retrospective studies were
included by Liu et al. in their meta-analysis.14 Pooled data
analysis found a better preservation of RF with Off-C PN
when compared with On-C PN (decreased eGFR WMD 5.81,
95% CI 1.80–9.81, P = 0.005), with minimal differences in
perioperative safety and similar oncological outcomes.14
Notwithstanding, authors included all retrospective studies
with intrinsic selection bias, small sample sizes and short-
term follow up.
More recently, the impact of unclamping techniques was
questioned.19–21 Shah et al. retrospectively analyzed data
from 315 patients (209 On-C PN vs 106 Off-C PN).19 A
short-term benefit in RF was achieved in the unclamped
cohort postoperatively; conversely there were no differences
in functional outcomes between the On-C and Off-C cohorts
beyond 6-month follow up.19 However, the quality of evi-
dence from that study was impaired by a significant propor-
tion of patients lost at follow up and significant heterogeneity
of baseline features between the two arms.19
Similarly, Rosen et al. in a PSM comparison between 82
On-C robotic PN patients versus 41 Off-C robotic PN cases
Off-C PN reported no differences in terms of RF at both discharge and
(n = 472) P-value† 1-year follow up.20 That study as well had a small sample
0.67 size, short follow up (median 9.2 months) and highly selected
cohort (T1a stage, with mean tumor size not >2 cm).20
372 (78.8) Conversely, a recent PSM analysis carried out with 240
34 (7.2) Italian patients reported some benefits of the unclamping
52 (11) technique in postoperative RF outcomes.21 Pedicle clamping
13 (2.8)
was found as an independent predictor of immediate (3 days
1 (0.2)
after surgery) and early (1 month after) RF impairment, but
the difference lost its statistical significance at the sixth
month and at longer follow-up periods (up to 40 months).21

(a) Cancer-specific survival (b) Overall survival

100% 100%

Surgical technique Surgical technique

80% 80%
Cancer-specific survival probability

On-clamp
On-clamp
Off-clamp
Overall survival probability

Off-clamp
Log rank P = 0.26 Log rank P = 0.18
60% 60%

40% Follow-up, mo 24 60 96 40% Follow-up, mo 24 60 96

On-clamp PN
On-clamp PN
- Probabilities ± SE 100 ± 0 100 ± 0 100 ± 0
- Probabilities ± SE 99.2 ± 0.8 94.9 ± 2.3 90.9 ± 4.4
- N at risk (events) 123 (0) 55 (0) 16 (0)
- N at risk (events) 123 (1) 55 (5) 16 (6)
20% 20%
Off-clamp PN
- Probabilities ± SE 99.7 ± 0.3 98.8 ± 0.7 98.8 ± 0.7 Off-clamp PN
- N at risk (events) 370 (1) 172 (3) 38 (3) - Probabilities ± SE 99 ± 0.6 98.5 ± 0.8 98.5 ± 0.8
- N at risk (events) 370 (3) 172 (4) 38 (4)
0% 0%

.00 12.00 24.00 36.00 48.00 60.00 72.00 84.00 96.00 .00 12.00 24.00 36.00 48.00 60.00 72.00 84.00 96.00
Follow-up (months) Follow-up (months)

Fig. 3 (a,b) Kaplan–Meier analysis showing CSS and OS of On-C and Off-C PSM selected cohorts.

© 2019 The Japanese Urological Association 5

G SIMONE ET AL.
However, in a subanalysis of 64 patients with Charlson
Comorbidity Index ≥2 (all patients with uncontrolled diabetes
type 2 belonged to this category by definition) despite normal
eGFR at baseline, the Off-C group showed a significantly
lower rate of RF impairment (reduction in eGFR >15%) dur-
ing the entire follow-up period (at 6 months 4% vs 13.5%,
P = 0.02; at last follow up 7.5% vs 15%, P = 0.01).21 Never-
theless, the threshold for impaired eGFR was only one (re-
duction in eGFR >15%), not allowing to precisely distinguish
the patients with severe reduction of RF from those with
moderate impairment. In addition, even in this study the fol-
low-up period did not exceed 40 months.21
The present better discriminates the degree of RF impair-
ment in different stages, according to CKD classification.
Furthermore, at the best of our knowledge, our study pre-
sented the longest follow-up period. We assessed the evolu-
tion of RF in patients undergoing elective PN up to 8 years,
whereas in previous studies the monitoring of RF did not
exceed 5 years. This is an aspect of certain interest, because
the longitudinal kinetics of RF continuously evolve over
time. Consistent with the vast majority of previous studies, in
the present series the unclamped group showed a favorable
trend in terms of RF with a short-term follow up, then main-
taining this plateau until the fifth year of monitoring after sur-
gery.12–14 However, it is precisely from the fifth year
onwards that the trend in favor of Off-C surgery becomes
increasingly evident (Fig. 1a,b). In detail, the probability of
developing a severe reduction of RF in the On-C PN passed
from 0.6% at 2 years to 15.5% after 8 years, whereas it was
rather stable over time in the Off-C cohort (2-, 5- and 8-year
risk 0.8%, 0.8% and 0.8%, respectively; Fig. 2). This is cer-
tainly the most important element of innovation provided by
the present study. According to our findings, the beneficial
effect of Off-C is evident after a short follow-up period, but
it is further accentuated after at least 5 years of follow up. In
the meantime, the contralateral kidney might overcome poten-
tial RF loss of the treated kidney, thus mimicking the absence
of ischemic injury. The rationale behind this association
between clamping techniques and the evolution of RF out-
comes over time remains unknown. Undoubtedly, RF evolu-
tion is time dependent, with age being a key variable to
assess eGFR. That being said, our cohort was initially
selected only including patients with baseline eGFR >60 mL/
min. Theoretically, this population should have a negligible
risk of developing significant stage 3b CKD (eGFR <45 mL/
min), therefore the main reason why a long follow-up period
was necessary to highlight these differences between arms is
obviously in the selection process. Notably, the study design
provides potential answers to a specific question: “Why carry
out Off-C PN in patients with baseline eGFR >60 mL/min?”.
The present data suggest a significantly higher probability of
developing new-onset stage 3b CKD at 5-year follow up.
Interestingly, the differences between arms were valid,
despite the minimal duration of the warm ischemia time in
the On-C group (mean 16 min). These data would confirm
the initial findings by Thompson et al. supporting WIT as a
continuous variable.21 Therefore, even early unclamping tech-
niques (generally accepted as WIT threshold <15 min)
seemed to have a significant impact on long-term RF.
6 © 2019 The Japanese Urological Association
Furthermore – consistent with previous literature and
showing the internal validity of the present results – age, dia-
betes, baseline eGFR and eGFR at discharge were significant
predictors of severe RF impairment on univariable analysis,
although on multivariable analysis only eGFR at discharge
and WI proved to be predictors of stage 3b CKD new-onset
during follow up.12–14,21
Nevertheless, the present study is not devoid of limitations.
First, all data were retrospectively analyzed. In addition, non-
random assignment bias was only mitigated with a PSM anal-
ysis. In addition, as the nephrometry scores were prospec-
tively and routinely collected since 2011, PSM analysis
accounted only for tumor size.22 Similarly, data about the
percentage of parenchyma spared after PN, recently shown as
a potential determinant of postoperative RF, were not avail-
able for the vast majority of patients.23 According to potential
differences in surgeons’ experience, which might concern the
reader, we assumed comparable experience of surgeons who
contributed to the cases here analyzed, being the two institu-
tions referral centers for PN.
Finally, the present study used eGFR with the MDRD for-
mula for estimating RF.15 In the setting of elective PN with a
normal contralateral kidney, a MAG3 renal scan is certainly a
more accurate method for evaluating the contribution of each
kidney to changes in RF, but unfortunately it was not avail-
able for a large proportion of the present patients.24
Despite all these limitations, the present study has several
strengths. In particular, with >600 patients enrolled, it had a
sufficiently large sample size to detect significant differences
between two arms, also including cT2 stage patients, thus
representing a wide clinical scenario of PN patterns in tertiary
referral centers. The long follow-up period provided clinically
meaningful information about RF evolution over time, with
the functional benefits of Off-C procedures being clinically
evident (new-onset stage 3b CKD) only at 5-year assessment.
According to the present findings, patients with impaired
RF preoperatively, patients with normal eGFR at baseline
associated with moderate/severe comorbidities and/or with an
expected long follow up should be adequately counseled, as
they could mostly benefit from Off-C procedures.
Nevertheless, definitive conclusions about the hypothetical
benefits of Off-C techniques over conventional On-C PN
require prospective randomized trials with long-term follow up.
In long-term follow up, Off-C PN is associated with a sig-
nificantly higher probability of maintaining 100% eGFR after
surgery compared with On-C PN in patients with cT1–2/N0/
M0 renal tumors and good baseline RF candidates for elec-
tive PN. Patients treated with On-C PN had a 7.3-fold
increased risk of developing a severe CKD during long term
follow up.
Conflict of interest
None declared.
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