European Journal of Nuclear Medicine and Molecular Imaging (2026) 53:5427–5435
https://doi.org/10.1007/s00259-026-07865-8
ORIGINAL ARTICLE
Could we reduce renal toxicity of [177Lu]Lu-PSMA radioligand therapy
with furosemide?
Sabin G. Pop1 · Klaus Strobel2 · Jakob Heimer1,3 · Chiara Baumann1 · Aurelius Omlin4 · Tatjana Leike2
Noel Spielhofer1 · Cristina E. Popescu1 · Andrea Zander2 · Irene A. Burger1,5,6
·
Received: 21 January 2026 / Accepted: 23 March 2026 / Published online: 1 April 2026
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2026
Abstract
Purpose Impaired renal function after [177Lu]Lu-PSMA radioligand therapy (RLT) is a growing concern as the field moves
toward earlier applications. Little is known how renal function could be protected. This study evaluates the impact of furosemide administered shortly after [177Lu]Lu-PSMA RLT, based on long-term follow-up of renal function and quantitative
assessment of renal uptake.
Methods Retrospective analysis of patients treated with a least 4 cycles of [177Lu]Lu-PSMA at two Swiss RLT centers
with 40 mg furosemide 30 min after injection (CenA) and without (CenB). CenA used [177Lu]Lu-PSMA-I&T and [177Lu]
Lu-PSMA-617, while CenB used only [177Lu]Lu-PSMA-I&T. A mixed-effects model was used to evaluate eGFR and PSA
change per cycle in the first cohort. To increase the number for renal uptake of [177Lu]Lu-PSMA-I&T in CenA, supplementary patients with less than 4 cycles were included for quantitative SPECT assessment.
Results In CenA, 24 patients with 5.4±0.8 doses (17 [177Lu]Lu-PSMA-617 / 7 [177Lu]Lu-PSMA-I&T) were followed over
202.0±58 days. In center CenB 20 patients with 5.4±0.9 doses were followed over 210.6±48 days. CenB showed a significant
drop in eGFR per cycle of -2 ml/min/1.73m2 (CI − 2.8/−1.1), p < 0.001, while CenA showed no significant decrease per cycle,
with 0.3 ml/min/1.73m2 (CI − 0.6/1.1), p = 0.587. For quantitative analysis 20 patients with [177Lu]Lu-PSMA-I&T in CenB
had a mean SUVpeak of 7.7±3.1, while 16 patients in CenA with [177Lu]Lu-PSMA-I&T had a mean SUVpeak of 7.1±3.0 and
17 patients with [177Lu]Lu-PSMA-617 had a mean of 6.2±1.8.
Conclusion Furosemide may reduce tracer accumulation in the kidneys after [177Lu]Lu-PSMA RLT. This might explain the
mostly stable eGFR values observed in CenA, while there was a significant drop in CenB, without furosemide. If diuretics
could reduce renal toxicity without impairing efficacy warrants further prospective evaluation.
Keywords Radioligand therapy · mCRPC · Diuretics · Nephrotoxicity · Quantitative SPECT
Andrea Zander and Irene A. Burger contributed equally to this work
and shared last authorship.
Irene A. Burger
Irene.burger@ksb.ch
1
2
Department of Nuclear Medicine, Kantonsspital Baden,
Affiliated Hospital for Research and Teaching of the Faculty
of Medicine of the University of Zurich, Baden
5404, Switzerland
Department of Nuclear Medicine and Radiology, Luzerner
Kantonsspital, University Teaching and Research Hospital,
University of Lucerne, Lucerne, Switzerland
3
Digital Trial Intervention Plattform (dTIP), ETH Zurich,
Zurich, Switzerland
4
Onkozentrum Zurich, University of Zurich and
Tumorzentrum Hirslanden Zurich, Zurich, Switzerland
5
Department of Nuclear Medicine, University Hospital
Zurich, University of Zurich, Zurich, Switzerland
6
Department of Health Sciences and Technology, ETH Zurich,
Zurich, Switzerland
13
5428
European Journal of Nuclear Medicine and Molecular Imaging (2026) 53:5427–5435
Introduction
The increased expression of Prostate-specific-membrane
Antigen (PSMA) on prostate cancer (PCa) cells has
become a target for various diagnostic and therapeutic
approaches. One being Lutetium-177 radioligand therapy (RLT), which is becoming increasingly important as
a therapy option in patients with metastatic castrationresistant prostate cancer (mCRPC). PSMA-targeting RLT
offers well-tolerated, targeted therapy with limited side
effects [1]. Therefore, applications and indications are
rapidly expanding [2, 3].
Following the phase 3 VISION and PSMAfore trial
[177Lu]Lu-PSMA RLT has been approved for mCRPC
before or after chemotherapy, where it has shown both
enhanced progression-free survival in both trials and
overall survival only in the VISION trial in patients with
mCPRC [1, 3]. Consequently, the question becomes apparent, whether an earlier indication of PSMA-RLT might be
beneficial. Early studies suggested no significant decrease
in renal function using [177Lu]Lu-PSMA-I&T even when
measured via functional renal scintigraphy in addition
to serum biomarkers [4]. However, the follow-up in this
cohort was limited to the duration of the RLT, with only
17 patients receiving 5 or more cycles [4]. Furthermore,
initial safety studies for using 6.8 GBq [177Lu]Lu-PSMAI&T did not indicate any relevant renal impairment, even
in patients with higher cumulative doses than 23 Gy [5].
The dosimetry study from the VISION trial revealed a
mean absorbed dose in the kidneys was 15 ± 5.8 Gy, concluding that a total of 44.4 GBq on 6 cycles should not
lead to renal toxicity, within 5.52 months [6]. Similarly, a
retrospective study of 110 patients, revealed no correlation
between cumulative renal dose and decrease in glomerular
filtration rate (GFR) during a follow up period of 6 weeks
after RLT, they did reduce the dose to 5.5–6.5 GBq per
cycle for patients with solitary kidneys or pre-existing
nephropathy (eGFR < 60 ml/min/1.73m2) [7].
Recently the data of a randomized phase 3 trial in metastatic hormone sensitive prostate cancer was presented at
ESMO 2025, showing a progression free survival benefit for
patients treated not only with androgen deprivation therapy
and an androgen receptor pathway inhibitor but additional
6 cycles of 7.4 GBq [177Lu]Lu-PSMA-617 (PSMAddition
Scott T. et al., ESMO 2025). However, the data also showed
that side effects and a decrease in well-being were observed
in the therapy arm beyond the expected dry mouth, which
affected 46.5% of patients. Grade 1–2 cytopenia was twice
as common in the therapy arm, and renal events occurred in
7.1% of patients compared to 4.6% in the control arm.
13
Therefore, especially for earlier applications, long term
side effects such as decrease of renal function might become
more relevant. Close attention should therefore be paid to
renal damage as one of the more identified side effects of
PSMA targeting RLT. Furthermore, when considering combination therapies involving either chemotherapy or hormone therapy, it is important to pay attention to the potential
loss of kidney function.
It has been suggested that the type of radio ligand used,
[177Lu]Lu-PSMA-617 or [177Lu]Lu-PSMA-I&T, might
influence the extent of renal functional impairment. This
assumption is based on dosimetry data showing a slightly
higher renal uptake for [177Lu]Lu-PSMA-I&T with a mean
absorbed kidney dose of 0.73 ± 0.33 Gy/GBq [5] compared
to 0.44 ± 0.21 Gy/GBq [6] with [177Lu]Lu-PSMA-617. Both
ligands are small-molecule inhibitors that target the enzymatic pocket of PSMA. However, their molecular structures
are dissimilar, with variance in the overall hydrophilicity
and protein binding, leading to divergent pharmacokinetic
and dosimetry profiles.
Nevertheless, reports comparing renal toxicity between
both RLT ligands could not document a significant difference in decrease in GFR [8, 9]. However, increasing long
term follow-up data show that a moderate decrease in eGFR
(30–40%) can be observed in 45% of the patients after one
year [10]. Furthermore, first reports on severe radiation
nephropathy 12–17 months after therapy in up to 10% of
patients receiving > 6 cycles of [177Lu]Lu-PSMA-I&T have
been published [11].
To reduce renal radiation exposure, strategies to increase
clearance from the kidneys might improve tolerability. Furosemide (Lasix©), a loop diuretic, inhibits the reabsorption of
electrolytes in the proximal and distal tubules, and increasing the volume of excretion, without increasing the renal
perfusion or GFR [12]. The faster excretion of [68Ga]GaPSMA-11 from the renal system has been well established
for imaging, therefore administration of 20 mg furosemide
i.v. just prior or after the administration of hydrophilic
PSMA PET ligands ([68Ga]Ga-PSMA-11, [18F]F-DCFPyl)
is part of the EANM guidelines for PSMA PET/CT imaging [13]. Therefore, Topal et al. suggested the use of 40 mg
furosemide after therapy in patients without contraindications [7]. Nevertheless, the use of furosemide for [177Lu]LuPSMA RLT was not part of the protocol in the initial trials.
The aim of this two-center retrospective analysis is to
evaluate the risk–benefit profile of furosemide administered
shortly after [177Lu]Lu-PSMA RLT, based on long term follow-up of renal function, but also quantitative assessment
of renal uptake based on SPECT/CT scans performed 48 h
after each therapy cycle.
European Journal of Nuclear Medicine and Molecular Imaging (2026) 53:5427–5435
Methods
Patient cohort
This retrospective, two-center comparative study was
designed to evaluate the impact of furosemide administration shortly after [177Lu]Lu-PSMA RLT on renal function
and therapeutic efficiency. Data were collected from two
Swiss nuclear medicine institutes: Kantonsspital Baden
(CenA) and Luzerner Kantonsspital (CenB), with approval
from the local ethics committee (BASEC 2025 − 00461).
Inclusion criteria were a signed general consent, a minimum of four cycles of [177Lu]Lu-PSMA RLT according
to the inclusion criteria of the VISION trial (mCRPC with
one/two lines of taxane or unfit for chemotherapy) and no
prior renal obstruction or nephrectomy. Renal function
was assessed using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula to estimate the
GFR (eGFR) before each treatment cycle and after therapy. The formula is as follows: eGFR = 141×min(Scr/k,1)a
× max(Scr/k,1)-1.209 × 0.993age (with k = 0.9, a = -0.411,
where min and max represent the minimum respectively
maximum values of Scr/k or 1) [14]. A decrease of at least
30% in eGFR was defined as clinically significant [15, 16].
Except for the administration of 40 mg furosemide, 30 min
after therapy application at CenA, the therapeutic protocols
were identical. The CenA cohort included patients treated
with either [177Lu]Lu-PSMA-I&T or [177Lu]Lu-PSMA-617.
The CenB cohort exclusively comprised patients treated
with [177Lu]Lu-PSMA-I&T. Given this imbalance in the
two radioligands used, and the significantly lower number
of patients undergoing [177Lu]Lu-PSMA-I&T with furosemide, for the quantitative assessment of renal and hepatic
uptake a supplementary cohort of CenA patients who had
undergone fewer than four therapy cycles was included in
the secondary analysis to achieve a balanced distribution of
patients.
Therapy protocol
Patients received [177Lu]Lu-PSMA therapy, administered
at 7.4 GBq per cycle with 6-week intervals (± 1 weeks).
Patients with a solitary kidney, were excluded from this
analysis. Extended (> 4) cycles were continued if both biochemical and imaging responses were observed and no
clinical or biochemical deterioration, due to potential side
effects occurred. The decision to proceed with extended
therapy was made by a multidisciplinary board.
Biochemical response was assessed by a PSA decline of at
least 50% 8–12 weeks after starting treatment. Imaging based
response was assessed using quantitative [177Lu]Lu-PSMA
5429
SPECT/CT after each cycle. [177Lu]Lu-PSMA therapy was
administered as a slow intravenous injection (3–5 min)
according to the European Association of Nuclear Medicine
(EANM) guidelines [17]. With each treatment, patients without history of cardiac conditions received intravenous hydration with 500–1000 ml of 0.9% NaCl. Sufficient hydration
was recommended in the weeks following treatment.
The therapy protocol was identical, except for the administration of 40 mg furosemide 30 min after RTL injection
in CenA, which was not performed in CenB. CenA used
[177Lu]Lu-PSMA-I&T and [177Lu]Lu-PSMA-617, while
CenB only used [177Lu]Lu-PSMA-I&T.
Outcome analysis
We screened the hospital information system for creatinine
and eGFR values, as well as PSA follow-up, during therapy
and follow-up. For external patients, referring physicians
were contacted to obtain latest renal function values.
Imaging protocol
In both centers, the post-therapy scan was performed on
the second day (48 h) after RLT application. Both centers
used a Symbia Intevo Bold SPECT/CT (Siemens Healthineers, Erlangen, Germany) with a MELP collimator. Utilizing the low-energy gamma emitted by Lu-177 (Eγ max
of 208 keV)., The examination consisted of whole-body
planar scintigraphy with ventral and dorsal acquisitions,
followed by partial-body SPECT/CT from the parotid
gland level to the patient’s pelvis (2–3 bed positions), with
a SPECT slice thickness of 2.0 mm, a matrix of 256 × 256
and an acquisition time of approximately 15 min per bed
(10 s. per View). Image reconstruction was performed
using xSPECTQuant for quantitative assessment of tracer
distribution. The reconstruction parameters were identical
for both centers, eight iterations with four subsets and 3D
Gaussian full width at half maximum (FWHM) filtering
(8.0 mm).
Image analysis
In a central readout all scans were reviewed for diagnostic
quality. If scan quality was approved, volumes of interest
(VOI) were placed around the kidneys by a nuclear medicine resident or medical student (SGP, CB) using Syngo.
Via VB80D©, making sure that there is no pathological
uptake of adjacent metastasis within the VOI (Fig. 1). All
VOIs and measurements were double checked by a senior
nuclear medicine physician and radiologist with over 16
years of experience (IAB). To quantify [177Lu]Lu-PSMA
13
5430
European Journal of Nuclear Medicine and Molecular Imaging (2026) 53:5427–5435
Fig. 1 Illustration of SPECT image analysis using spheroid volumes of interest covering the entire kidneys, without inclusion of extra-renal tracer
accumulation. For further analysis SUVpeak was selected
accumulation SUVpeak was selected to minimize impact of
VOI size on SUVmean and reduce variability over SUVmax
[18, 19].
Results
Statistics
In the first cohort, including only patients receiving at
least four cycles of [177Lu]Lu-PSMA RLT, 24 patients
were identified in CenA with a mean of 5.4±0.8 doses (17
[177Lu]Lu-PSMA-617 and 7 [177Lu]Lu-PSMA-I&T), average follow-up was 202.0±58 days. In CenB 20 patients
with a mean of 5.4±0.9 doses were identified and followed over a mean of 210.6±48 days. Baseline eGFR
and PSA values were not significantly different between
both centers. The mean administered dose was 7.3 ± 0.1
GBq (CenA) and 7.4 ± 0.2 GBq (CenB), this difference
reached statistical significance despite the similar values
(p = 0.002) (Table 1).
Continuous variables were summarized as mean ± standard
deviation (SD) and categorical variables as frequencies
(%). Differences in baseline values were assessed using the
Wilcoxon rank-sum test or Fisher’s exact test. Longitudinal
changes in eGFR and log2-transformed PSA were analyzed
using linear mixed-effects models (LMM). These models
included fixed effects for Therapy cycle, Center/Substance
Group, dose, as well as age and baseline values. Interactions between cycle and Substance, baseline values, and
dose were modeled. A random intercept was included for
patient_id to account for repeated measures. Pairwise contrasts of the slopes were calculated using estimated marginal
means. Differences in organ uptake (SUVpeak) were analyzed using LMMs adjusted for baseline eGFR, cycle, and
age. All analyses were performed using R (version 4.4.1).
P-values < 0.05 were considered statistically significant.
13
Patient cohort
Impact on renal function and PSA
Based on the mixed-effects model, there was no significant decrease in eGFR per cycle in CenA with the addition of furosemide, with 0.3 ml/min/1.73m2 (CI − 0.6,
European Journal of Nuclear Medicine and Molecular Imaging (2026) 53:5427–5435
Table 1 Patient characteristics for outcome analysis
Characteristic
CenA,1
CenB,1
N = 24
N = 20
Age
76.6 (7.2) 73.9 (8.1)
Baseline PSA
124.3
138.7
(181.8)
(220.5)
Baseline eGFR
71.0 (15.4) 74.4 (16.0)
Total Cycles
4
5 (21%)
5 (25%)
5
5 (21%)
2 (10%)
6
14 (58%) 13 (65%)
After therapy Follow-up
228.8
301.3
(Days)
(215.8)
(234.2)
Baseline Kidney SUVpeak
6.4 (1.8)
7.7 (3.1)*
Baseline Liver SUVpeak
0.9 (0.4)
0.8 (0.6)*
Dose (GBq)
7.3 (0.1)
7.4 (0.2)
1
Mean (SD); n (%)
p-value2
0.2
0.6
0.5
0.7
5431
Table 2 Outcome trends eGFR and PSA
Metric
Group Slope [95% CI]
eGFR Slope
log2(PSA)
Slope
CenA
CenB
CenA
CenB
0.3 [-0.6, 1.1]
-2.0 [-2.9, -1.0]
-0.56 [-0.68, -0.43]
-0.36 [-0.51, -0.21]
p-value
(vs. 0)
0.587
< 0.001
< 0.001
< 0.001
p-value
(vs. Ref)
—
< 0.001
—
0.047
Impact on renal and hepatic uptake
0.3
0.2
0.2
0.002
2
Wilcoxon rank sum test; Fisher’s exact test; Wilcoxon rank sum
exact test
*Not available in 2 patients
1.1), p = 0.587, while a significant drop in eGFR per cycle
was observed in CenB of -2.0 ml/min/1.73m2 (CI − 2.9,
− 1.0), p < 0.001 (Fig. 2A; Table 2). The average eGFR
decrease between baseline and last follow up in CenA
was − 6.5±19 ml/min/1.73m2, while in CenB an average decrease of – 20±20 ml/min/1.73m2 was observed.
Neither dose nor age had an impact on eGFR changes.
In contrast, PSA decline was observed in both centers,
with a more pronounced decline in CenA compared to
CenB (log(PSA) of CenA − 0.56 (CI − 0.68, − 0.43) and
CenB − 0.36 (CI-0.51, − 0.21), (p = 0.047)) (Table 2;
Fig. 2B).
To consider potential differences between both RLT ligands
in distribution for the quantitative analysis of kidney uptake,
additional patients with less than 4 cycles were included in
CenA, to create a more balanced cohort. This resulted in
16 patients in CenA with [177Lu]Lu-PSMA-I&T and 17
receiving [177Lu]Lu-PSMA-617 compared to 20 patients
in CenB treated with [177Lu]Lu-PSMA-I&T without furosemide (Table 3). The mean renal uptake 48 h after injection of [177Lu]Lu-PSMA-I&T at baseline with furosemide
was SUVpeak 7.1±3.0, while in CenB the uptake of [177Lu]
Lu-PSMA-I&T without furosemide was higher 7.7±3.1.
Also, for [177Lu]Lu-PSMA-617 with furosemide the uptake
was lower compared to CenB with SUVpeak 6.2±1.8.
Pairwise comparison of the mixed-effects model for
renal uptake, reached significance only between [177Lu]
Lu-PSMA-617 in CenA with furosemide, in comparison to
[177Lu]Lu-PSMA-I&T in CenB without furosemide (estimated difference of 1.69 [0.20,33.18], p = 0.027). There was
no significant difference between [177Lu]Lu-PSMA-617
and [177Lu]Lu-PSMA-I&T if given diuretics, or for [177Lu]
Lu-PSMA-I&T with or without diuretics (Fig. 3; Table 4).
Fig. 2 Trajectories for eGFR (A) and log2-transformed PSA (B) using linear mixed-effects models. These models included fixed effects for therapy
cycle, Center/Substance Group, and their interactions, as well as age and baseline values (eGFR, PSA)
13
5432
Table 3 Patient characteristics for quantitative analysis
Characteristic CenA
CenA
CenB
PSMAPSMAPSMA617,1N = 17 I&T,1N = 16 I&T,1N = 20
Age
76.4 (7.7)
78.6 (6.5)
73.9 (8.1)
Baseline PSA
92.1 (116.7) 244.7
138.7
(372.6)
(220.5)
Baseline eGFR 71.3 (17.4) 72.7 (12.3) 74.4 (16.0)
Total Cycles
1
0 (0%)
4 (25%)
0 (0%)
2
0 (0%)
3 (19%)
0 (0%)
3
0 (0%)
2 (13%)
0 (0%)
4
3 (18%)
2 (13%)
5 (25%)
5
3 (18%)
2 (13%)
2 (10%)
6
11 (65%)
3 (19%)
13 (65%)
Total Follow452.5
217.9
511.9
up (Days)
(264.6)
(193.0)
(249.3)
Therapy Dura- 211.1 (61.5) 90.1 (90.2) 210.6 (48.3)
tion (Days)
After therapy
241.4
127.8
301.3
Follow-up
(240.2)
(125.6)
(234.2)
(Days)
Baseline Kid6.2 (1.8)
7.1 (3.0)
7.7 (3.1)*
ney SUVpeak
Baseline Liver 1.0 (0.4)
0.6 (0.3)
0.8 (0.6)*
SUVpeak
1
Mean (SD); n (%)
2
European Journal of Nuclear Medicine and Molecular Imaging (2026) 53:5427–5435
p-value2
0.15
0.5
0.8
0.003
Table 4 Kidney SUVpeak analysis
Term
(CenA PSMA-617) - (CenA
PSMA-I&T)
(CenA PSMA-617) - (CenB
PSMA-I&T)
(CenA PSMA-I&T) - (CenB
PSMA-I&T)
Estimate_CI
-0.52 [-1.86,
0.82]
-1.69 [-3.14,
-0.23]
-1.17 [-2.67,
0.33]
p-value
0.450
0.027
0.133
For liver accumulation there was no significant difference
for [177Lu]Lu-PSMA-I&T in SUVpeak between both centers
with 0.6±0.3 in CenA, compared to 0.8±0.6 for CenB.
Significant eGFR decrease
0.001
< 0.001
0.062
0.3
0.016
Kruskal-Wallis rank sum test; Fisher’s exact test
*Not available in 2 patients
A significant decrease of more than 30% in eGFR was
observed in 2/24 (8%) patients in CenA. In both cases, eGFR
was not impaired at the beginning of the therapy with a
creatinine of 103 µmol/l / eGFR 63 ml/min/1.73m2 (in one
patient) and a creatinine of 80 µmol/l and eGFR of 87 ml/
min/1.73m2 (in the other). Four patients were treated with an
initial eGFR < 60 ml/min/1.73m2 (range 46–56) without dose
reduction. Over a mean follow-up time of 301±120 days none
of these patients had a relevant decline in renal function.
In CenB a decline of more than 30% in eGFR was
observed in 5/20 (25%). Only one of the five patients had
an eGFR < 60 ml/min/1.73m2 at the first cycle (53 ml/
min/1.73m2), the other 4 patients had creatinine values in
normal range (66–91 µmol/l). The patient in CenB with the
lowest renal function at first cycle with a creatinine of 151
and an eGFR of 36 ml/min/1.73m2 remained stable over 4
cycles and a follow time of 167 days.
Discussion
Fig. 3 Renal uptake of [177Lu]Lu-PSMA-617 with furosemide was
lower compared to [177Lu]Lu-PSMA-I&T with furosemide in CenA
(not reaching significance). Comparing [177Lu]Lu-PSMA-I&T
between both center, furosemide reduced the uptake, also not reaching
statistical significance
13
Increasing urinary volume with diuretics given shortly after
injection seems to protect renal function during PSMARLT. This is suggested by the significant difference in eGFR
reduction on long-term follow-up, seen between two centers
that followed the same RLT protocol except the additional
administration of 40 mg furosemide 30 min after injection
at CenA. This is also reflected with a trend to higher uptake
in the kidneys 48 h after injection on post-therapy scans in
patients treated with [177Lu]Lu-PSMA-I&T without furosemide, compared to [177Lu]Lu-PSMA-I&T with diuretics.
This is the first analysis looking into a potential impact of
diuretics on renal function during [177Lu]Lu-PSMA-directed
RLT with a long term follow up.
Our quantitative analysis revealed a stepwise
increase in accumulation from [177Lu]Lu-PSMA-617 to
[177Lu]Lu-PSMA-I&T with furosemide and to [177Lu]
European Journal of Nuclear Medicine and Molecular Imaging (2026) 53:5427–5435
Lu-PSMA-I&T without furosemide. Both steps did not
reach significance but are in line with the hypothesis that
furosemide is reducing the activity for [177Lu]Lu-PSMAI&T and that [177Lu]Lu-PSMA-I&T has a higher renal
accumulation compared to [177Lu]Lu-PSMA-I&T-617. This
finding is consistent with the higher tracer accumulation in
post-therapy dosimetry for [177Lu]Lu-PSMA-I&T compared
to [177Lu]Lu-PSMA-617 observed by other groups [8, 20].
Schuchardt et al. compared dose distribution and toxicity in
138 patients treated without diuretics. 51 received [177Lu]
Lu-PSMA-I&T and 87 had [177Lu]Lu-PSMA-617, with the
result that [177Lu]Lu-PSMA-I&T had a marginally higher
dose of 0.8 Gy/GBq compared to [177Lu]Lu-PSMA-617
with 0.9 Gy/GBq. However, this did not result in a significant difference in renal toxicity between both groups during
the observation period [8]. Similarly Hartrampf et al. did not
observe a significant difference in renal toxicity in a bicentric matched-pair analysis between 55 patients treated with
[177Lu]Lu-PSMA-617 and 55 undergoing RLT with [177Lu]
Lu-PSMA-I&T with comparable overall survival [9].
In our cohort, a significant decrease of more than 30%
in eGFR was observed in only 8% of patients in CenA,
compared to 25% in CenB, despite a higher number of
patients with an eGFR < 60 ml/min/1.73m2 at first cycle in
CenA (n = 4) compared to CenB (n = 1). This is consistent
with previous observations, that there is only a weak association between a decline of more than 30% after [177Lu]
Lu-PSMA-I&T and baseline eGFR value [21]. Steinfelder et
al. found that the mean eGFR was not significantly lower for
patients with renal decline, with 70.8±14.7 ml/min/1.73m2
compared to 78.3±18.0 ml/min/1.73m2 in patients without
(p = 0.01) [21, 22].
There are chemical differences between [177Lu]
Lu-PSMA-I&T and [177Lu]Lu-PSMA-617. [177Lu]
Lu-PSMA-I&T was developed for dual labeling with an
additional Iodine that could be used for imaging or therapy.
The radionuclide conjugation is based on four COO- groups,
leading to an overall negative charge of the chelator, this
is compensated with a long connecting arm to the binding
moiety, rendering [177Lu]Lu-PSMA-I&T a bit more polar
and less lipophilic compared to [177Lu]Lu-PSMA-617 [23,
24]. This might also explain the slightly higher tracer uptake
in the liver parenchyma observed for [177Lu]Lu-PSMA-617
in our cohort.
Regarding PSA decline, we did not observe any impairment due to the use of furosemide. In the analysis PSA reduction was deeper in CenA compared to CenB. Whether this is
due to the higher number of patients undergoing [177Lu]LuPSMA-617 compared to [177Lu]Lu-PSMA-I&T is unclear
and would be contradicted with other matched pair analyses
that did not observe any differences in outcomes [9].
5433
Potential applications for renal protection during PSMAdirected RLT are sparse. Kristiansson et al. suggest using
antioxidant α1-Microglobulin to improve renal function
after [177Lu]Lu-PSMA-617, but this was tested only in a
preclinical model in tumor-bearing mice [25, 26]. Others
suggested using Mannitol injections to increase diuresis in
a prospective study of 9 patients with only a slight, nonsignificant reduction in renal dose [27]. Given that furosemide
is a well-established therapy with limited toxicity and drug
interactions, this seems a more practical alternative.
This retrospective, multicenter study had a relatively
small size, two different ligands and without multiple timepoint dosimetry. Furthermore, the ligands were not distributed homogeneously between both centers, leading to
a cofounder for the analysis. However, Both centers have
the same scanner and imaging protocol, using quantitative
assessment of [177Lu]Lu-PSMA SPECT data. An increasing amount of literature and data suggests that a reasonable
approximation for total dose can be achieved, based on
single time point quantitative imaging. We therefore considered SUVpeak a good surrogate marker to compare renal
dose, using centralized readout, identical scanner equipment
as well as imaging protocols. Comparative studies on toxicity involving different radioligands are very difficult to
interpret. Small cohorts and numerous clinical variables can
confound such findings. We therefore chose a linear mixed
model to incorporate clinical parameters such as age, basal
renal function and number of cycles, to estimate the impact
of a single therapy cycle, with or without furosemide, on
eGFR.
Conclusion
Furosemide is reducing tracer accumulation in the kidneys
on post-therapy scans of [177Lu]Lu-PSMA RLT. Higher
renal uptake might explain the significant decrease in eGFR
observed in CenB not using furosemide, that was not seen in
CenA. Whether diuretics have the potential to reduce renal
toxicity without negative impact on antitumor efficacy warrants prospective evaluation.
Supplementary Information The online version contains supplementary
material available at ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​0​0​7​​/​s​0​​0​2​5​9​-​0​2​6​-​0​7​8​6​5​-​8.
Authors’ contributions Irene A. Burger, Andrea Zander, Klaus Strobel
and Sabin G. Pop contributed to the study conception and design. Material preparation (Noel Spielhofer, Cristina Popescu, Andrea Zander),
data collection (Sabin G. Pop, Chiara Baumann, Aurelius Omlin, Tatjana Leike). Data analysis was performed by Jakob Heimer and Sabin
G. Pop. The first draft of the manuscript was written by Sabin G. Pop
and Irene A. Burger and all authors commented on previous versions
of the manuscript. All authors read and approved the final manuscript.
13
5434
European Journal of Nuclear Medicine and Molecular Imaging (2026) 53:5427–5435
Funding This work was supported by the ForMe program (Association for Medical Research and Innovation in the Canton of Aargau).
9.
Data availability The datasets generated during and/or analysed during the current study are available from the corresponding author on
reasonable request.
Declarations
Ethics approval and consent to participate The cantonal ethics committee approved this study for both centers. All data was exchanged
with study numbers only, in adherence to local and the ethical standards as laid down in the Helsinki declaration and its later amendments.
All patients included in this analysis gave their general consent for
retrospective use of their data.
10.
11.
12.
13.
Competing interests All authors confirm no conflicts of interest, or
financial interest relevant for this work.
14.
References
1.
2.
3.
4.
5.
6.
7.
8.
Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for
Metastatic Castration-Resistant Prostate Cancer. N Engl J Med.
2021;385(12):1091–103. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​0​5​6​​/​N​E​​J​M​o​a​2​1​0​7​3​
2​2.
Emmett L, Subramaniam S, Crumbaker M, et al. [(177)Lu]
Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an openlabel, multicentre, randomised, phase 2 trial. Lancet Oncol.
2024;25(5):563–71. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​0​1​6​​/​S​1​​4​7​0​-​2​0​4​5​(​2​4​)​0​0​1​
3​5​-​9.
Morris MJ, Castellano D, Herrmann K, et al. (177)Lu-PSMA-617
versus a change of androgen receptor pathway inhibitor therapy
for taxane-naive patients with progressive metastatic castrationresistant prostate cancer (PSMAfore): a phase 3, randomised,
controlled trial. Lancet. 2024;404(10459):1227–39. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​
r​g​/​​1​0​.​1​​0​1​6​​/​S​0​​1​4​0​-​6​7​3​6​(​2​4​)​0​1​6​5​3​-​2.
Hartrampf PE, Weinzierl FX, Serfling SE, et al. Hematotoxicity and Nephrotoxicity in Prostate Cancer Patients Undergoing
Radioligand Therapy with [(177)Lu]Lu-PSMA I&T. Cancers
(Basel). 2022;14(3). ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​3​​3​9​0​​/​c​a​​n​c​e​r​s​1​4​0​3​0​6​4​7.
Hansen AR, Probst S, Beauregard JM, et al. Initial clinical
experience with [(177)Lu]Lu-PNT2002 radioligand therapy in
metastatic castration-resistant prostate cancer: dosimetry, safety,
and efficacy from the lead-in cohort of the SPLASH trial. Front
Oncol. 2024;14:1483953. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​3​​3​8​9​​/​f​o​​n​c​.​2​0​2​4​.​1​4​8​
3​9​5​3.
Herrmann K, Rahbar K, Eiber M, et al. Renal and Multiorgan
Safety of (177)Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer in the VISION Dosimetry Substudy. J Nucl Med. 2024;65(1):71–8. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​2​​9​6​7​​/​j​n​​u​
m​e​d​.​1​2​3​.​2​6​5​4​4​8.
Topal E, Kovan B, Iribas A, et al. Impact of extended [(177)Lu]
Lu-PSMA-617 therapy on absorbed kidney dose and CKD-EPI
values: how long can therapy be safely continued? Eur J Nucl
Med Mol Imaging. 2025;52(9):3135–44. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​0​0​7​​/​
s​0​​0​2​5​9​-​0​2​5​-​0​7​1​2​5​-​1.
Schuchardt C, Zhang J, Kulkarni HR, Chen X, Muller D, Baum
RP. Prostate-Specific Membrane Antigen Radioligand Therapy
Using (177)Lu-PSMA I&T and (177)Lu-PSMA-617 in Patients
with Metastatic Castration-Resistant Prostate Cancer: Comparison of Safety, Biodistribution, and Dosimetry. J Nucl Med.
13
15.
16.
17.
18.
19.
20.
21.
22.
23.
2022;63(8):1199–207. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​2​​9​6​7​​/​j​n​​u​m​e​d​.​1​2​1​.​2​6​2​7​
1​3.
Hartrampf PE, Weinzierl FX, Buck AK, et al. Matched-pair analysis of [(177)Lu]Lu-PSMA I&T and [(177)Lu]Lu-PSMA-617 in
patients with metastatic castration-resistant prostate cancer. Eur J
Nucl Med Mol Imaging. 2022;49(9):3269–76. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​
1​​0​0​7​​/​s​0​​0​2​5​9​-​0​2​2​-​0​5​7​4​4​-​6.
Steinhelfer L, Lunger L, Cala L, et al. Long-Term Nephrotoxicity of (177)Lu-PSMA Radioligand Therapy. J Nucl Med.
2024;65(1):79–84. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​2​​9​6​7​​/​j​n​​u​m​e​d​.​1​2​3​.​2​6​5​9​8​6.
Schafer H, Mayr S, Buttner-Herold M, et al. Extensive (177)LuPSMA Radioligand Therapy Can Lead to Radiation Nephropathy
with a Renal Thrombotic Microangiopathy-like Picture. Eur Urol.
2023;83(5):385–90. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​0​1​6​​/​j​.​​e​u​r​u​r​o​.​2​0​2​2​.​0​5​.​0​2​5.
Benet LZ. Pharmacokinetics/pharmacodynamics of furosemide
in man: a review. J Pharmacokinet Biopharm. 1979;7(1):1–27. ​h​t​
t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​0​0​7​​/​B​F​​0​1​0​5​9​4​3​8.
Fendler WP, Eiber M, Beheshti M, et al. PSMA PET/CT: joint
EANM procedure guideline/SNMMI procedure standard for
prostate cancer imaging 2.0. Eur J Nucl Med Mol Imaging.
2023;50(5):1466–86. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​0​0​7​​/​s​0​​0​2​5​9​-​0​2​2​-​0​6​0​8​9​-​w.
Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. N Engl J
Med. 2021;385(19):1737–49. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​0​5​6​​/​N​E​​J​M​o​a​2​1​
0​2​9​5​3.
Coresh J, Turin TC, Matsushita K, et al. Decline in estimated
glomerular filtration rate and subsequent risk of end-stage renal
disease and mortality. JAMA. 2014;311(24):2518–31. ​h​t​t​p​​s​:​/​​/​d​o​i​​
.​o​​r​g​/​​1​0​.​1​​0​0​1​​/​j​a​​m​a​.​2​0​1​4​.​6​6​3​4.
Levey AS, Gansevoort RT, Coresh J, et al. Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of
CKD: A Scientific Workshop Sponsored by the National Kidney
Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency. Am J Kidney Dis.
2020;75(1):84–104. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​0​5​3​​/​j​.​​a​j​k​d​.​2​0​1​9​.​0​6​.​0​0​9.
Kratochwil C, Fendler WP, Eiber M, et al. EANM procedure
guidelines for radionuclide therapy with (177)Lu-labelled PSMAligands ((177)Lu-PSMA-RLT). Eur J Nucl Med Mol Imaging.
2019;46(12):2536–44. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​0​0​7​​/​s​0​​0​2​5​9​-​0​1​9​-​0​4​4​8​5​-​3.
Laffon E, Burger IA, Lamare F, de Clermont H, Marthan R. SUVpeak Performance in Lung Cancer: Comparison to Average SUV
from the 40 Hottest Voxels. J Nucl Med. 2016;57(1):85–8. ​h​t​t​p​​s​:​/​​
/​d​o​i​​.​o​​r​g​/​​1​0​.​2​​9​6​7​​/​j​n​​u​m​e​d​.​1​1​5​.​1​6​1​9​6​8.
Burger IA, Huser DM, Burger C, von Schulthess GK, Buck A.
Repeatability of FDG quantification in tumor imaging: averaged
SUVs are superior to SUVmax. Nucl Med Biol. 2012;39(5):666–
70. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​0​1​6​​/​j​.​​n​u​c​​m​e​d​​b​i​o​.​​2​0​​1​1​.​1​1​.​0​0​2.
Uijen MJM, Prive BM, van Herpen CML, et al. Kidney absorbed
radiation doses for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]
Lu-PSMA-I&T determined by 3D clinical dosimetry. Nucl Med
Commun. 2023;44(4):270–5. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​0​9​7​​/​M​N​​M​.​0​0​0​
0​0​0​0​0​0​0​0​0​1​6​5​8.
Rosar F, Kochems N, Bartholoma M, et al. Renal Safety of [(177)
Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Compromised Baseline Kidney Function. Cancers (Basel). 2021;13(12).​
h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​3​​3​9​0​​/​c​a​​n​c​e​r​s​1​3​1​2​3​0​9​5.
Steinhelfer L, Jungmann F, Nickel M, et al. Automated CT Measurement of Total Kidney Volume for Predicting Renal Function
Decline after (177)Lu Prostate-specific Membrane Antigen-I&T
Radioligand Therapy. Radiology. 2025;314(2):e240427. ​h​t​t​p​​s​:​/​​/​d​
o​i​​.​o​​r​g​/​​1​0​.​1​​1​4​8​​/​r​a​​d​i​o​l​.​2​4​0​4​2​7.
Benesova M, Schafer M, Bauder-Wust U, et al. Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with
Optimized Linker Moiety for Imaging and Endoradiotherapy of
Prostate Cancer. J Nucl Med. 2015;56(6):914–20. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​
1​0​.​2​​9​6​7​​/​j​n​​u​m​e​d​.​1​1​4​.​1​4​7​4​1​3.
European Journal of Nuclear Medicine and Molecular Imaging (2026) 53:5427–5435
24. Weineisen M, Schottelius M, Simecek J, et al. 68Ga- and 177LuLabeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies. J
Nucl Med. 2015;56(8):1169–76. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​2​​9​6​7​​/​j​n​​u​m​e​d​
.​1​1​5​.​1​5​8​5​5​0.
25. Kristiansson A, Orbom A, Ahlstedt J, et al. (177)Lu-PSMA-617
Therapy in Mice, with or without the Antioxidant alpha(1)Microglobulin (A1M), Including Kidney Damage Assessment
Using (99m)Tc-MAG3 Imaging. Biomolecules. 2021;11(2). ​h​t​t​p​​s​
:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​3​​3​9​0​​/​b​i​​o​m​1​1​0​2​0​2​6​3.
26. Kristiansson A, Vilhelmsson Timmermand O, Altai M, Strand
SE, Akerstrom B, Orbom A. Hematological and renal toxicity in
mice after three cycles of high activity [(177)Lu]Lu-PSMA-617
with or without human alpha(1)-microglobulin. Sci Rep.
2024;14(1):10787. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​0​3​8​​/​s​4​​1​5​9​8​-​0​2​4​-​6​1​3​7​0​-​2.
5435
27. Sarnelli A, Belli ML, Di Iorio V, et al. Dosimetry of (177)
Lu-PSMA-617 after Mannitol Infusion and Glutamate Tablet
Administration: Preliminary Results of EUDRACT/RSO 2016002732-32 IRST Protocol. Molecules. 2019;24(3). ​h​t​t​p​s​:​​​/​​/​d​o​​i​.​o​​r​​g​​
/​​1​0​​.​3​3​​​9​0​/​​m​o​l​e​c​u​l​e​s​2​4​0​3​0​6​2​1.
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Springer Nature or its licensor (e.g. a society or other partner) holds
exclusive rights to this article under a publishing agreement with the
author(s) or other rightsholder(s); author self-archiving of the accepted
manuscript version of this article is solely governed by the terms of
such publishing agreement and applicable law.
13