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\begin{document}

\title{Transcutaneous Near Infra-Red Spectroscopy (NIRS) for monitoring
paediatric renal allograft perfusion}



\author[1]{Filippo Ghidini}%
\author[1]{Elisa Benetti}%
\author[1]{Pietro Zucchetta}%
\author[1]{Piergiorgio Gamba}%
\author[2]{Marco Castagnetti}%
\affil[1]{University of Padua}%
\affil[2]{Univeristy of Padua}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\selectlanguage{english}
\begin{abstract}
Background. The use of transcutaneous near-infrared spectroscopy (NIRS)
for the monitoring of the perfusion of renal allografts in paediatric
population has been proposed in the last years. This device might detect
early decrease in allograft oxygenation allowing prompt detection of
vascular complications. Methods. A systematic review of literature about
the use of transcutaneous NIRS in monitoring allograft perfusion was
performed according to the PRISMA guidelines. Results. The authors
screened 1313 papers. The search yielded five pertinent articles. Three
of them reported the experience of NIRS in kidney transplantation, for a
total of 53 paediatric patients and 50 adults. In these studies, NIRS
measurements was significantly related to serum creatinine, estimated
glomerular filtration rate (eGFR), urinary neutrophil
gelatinase-associated lipocalin (u-NGAL), serum lactate, resistive index
assessed by doppler-ultrasonography and systolic blood pressure. In the
paediatric studies no vascular complications were encountered.
Conclusions. Preliminary studies have related NIRS monitoring to renal
allograft perfusion and function. Further investigation is needed to
establish the normal range of NIRS values for renal allografts and the
factors influencing NIRS monitoring.%
\end{abstract}%



\sloppy


\emph{Short Report}

\textbf{Transcutaneous Near Infra-Red Spectroscopy (NIRS) for monitoring
paediatric renal allograft perfusion}

Filippo Ghidini\textsuperscript{1,2}, Elisa Benetti\textsuperscript{3},
Pietro Zucchetta\textsuperscript{4}, Piergiorgio
Gamba\textsuperscript{2}, Marco Castagnetti\textsuperscript{1,5}

\textsuperscript{1} Paediatric Urology, Department of Women's and
Children's Health; University of Padua, Italy

\textsuperscript{2} Paediatric Surgery, Department of Women's and
Children's Health; University of Padua, Italy

\textsuperscript{3} Paediatric Nephrology, Department of Women's and
Children's Health; University of Padua, Italy

\textsuperscript{4} Nuclear Medicine. Department of Medicine; University
of Padua, Italy

\textsuperscript{5} Department of Surgery, Oncology, and
Gastroenterology; University of Padova, Padua, Italy

\emph{Corresponding Author} : Filippo Ghidini

Department of Women's and Children's Health, University of Padua, Italy

via Nicol\selectlanguage{ngerman}ò Giustiniani, 35121 Padua, Italy

+393495313815

filippo.ghidini@studenti.unipd.it

Abstract word counts: 177

Main text word counts: 1055

References: 15

Table: 1

Supplementary materials: 2

\textbf{Running Head Title.} NIRS for paediatric kidney transplantation

\textbf{Abstract}

\emph{Background.} The use of transcutaneous near-infrared spectroscopy
(NIRS) for the monitoring of the perfusion of renal allografts in
paediatric population has been proposed in the last years. This device
might detect early decrease in allograft oxygenation allowing prompt
detection of vascular complications.

\emph{Methods.} A systematic review of literature about the use of
transcutaneous NIRS in monitoring allograft perfusion was performed
according to the PRISMA guidelines.

\emph{Results.} The authors screened 1313 papers. The search yielded
five pertinent articles. Three of them reported the experience of NIRS
in kidney transplantation, for a total of 53 paediatric patients and 50
adults. In these studies, NIRS measurements was significantly related to
serum creatinine, estimated glomerular filtration rate (eGFR), urinary
neutrophil gelatinase-associated lipocalin (u-NGAL), serum lactate,
resistive index assessed by doppler-ultrasonography and systolic blood
pressure. In the paediatric studies no vascular complications were
encountered.

\emph{Conclusions.} Preliminary studies have related NIRS monitoring to
renal allograft perfusion and function. Further investigation is needed
to establish the normal range of NIRS values for renal allografts and
the factors influencing NIRS monitoring.

\textbf{Keywords}

Near Infra-Red Spectroscopy, kidney transplantation, thrombosis,
doppler-ultrasonography

\textbf{Declarations}

\emph{Funding} . None declared.

\emph{Conflict of Interest} . None declared.

\emph{Authors' contribution.} All Authors contributed to the study
conception and design. FG and MC performed the literature search and the
screening of the papers. FG and MC wrote the first draft of the
manuscript. EB, PZ and PG critically reviewed and commented the previous
version of the manuscript. All authors read and approved the final
manuscript.

\textbf{Introduction}

Kidney transplantation (KT) has become the treatment of choice for
paediatric end-stage renal disease {[}1{]}. Nevertheless, in comparison
to adults, the small caliber of the vessels and the common size-mismatch
between donors and recipients can predispose to vascular complications
including allograft thrombosis. The latter may affect up to 10\% of KTs
and account for 35\% of allograft losses in the first year {[}2{]}.
Prompt recognition and treatment is clearly essential for the
preservation of the allograft.

Vascular complications have no specific clinical or biochemical signs
allowing for early diagnosis. Doppler-ultrasonography (DUS) and renal
scintigraphy are reliable tools to assess allograft perfusion {[}3{]},
but do not allow for continuous monitoring of the allograft and can miss
early diagnosis, even if performed with a strict schedule in early
follow-up of KT {[}4{]}.

Transcutaneous near-infrared spectroscopy (NIRS) allows for
non-invasive, real-time, continuous monitoring of regional oxygenation
of the haemoglobin (rSrO2), which is an indirect measure of the blood
flow and the metabolic state, of tissue placed deeper beyond the skin.
Several clinical studies have tested the use of NIRS for monitoring
cerebral and somatic perfusion in intensive care units {[}5{]} and the
viability of soft-tissue flaps {[}6{]}. Recently, it has been proposed
for the surveillance of allograft perfusion too {[}7{]}.

A systematic search of literature was performed, aiming to identify the
current evidence on the \emph{in vivo} application of NIRS for the
monitoring of allograft perfusion. The findings might be useful for
future research to implement the large-scale use of NIRS.

\textbf{Materials and Methods}

The systematic review was performed according to the PRISMA guidelines
{[}8{]}. PubMed, Scopus and The Cochrane Library were searched in
November 2020, using a combination of terms including ``near-infrared
spectroscopy'', ``NIRS'' and ``transplantation''. The search was limited
to English language and publications from 1991 to 2020. Studies
including animal models were excluded.

\textbf{Results}

Overall, 1313 papers were screened. The search yielded only five
pertinent articles (\emph{Appenice A} ). Three of them investigated
renal graft perfusion, accounting for a total of 53 paediatric patients
and 50 adult patients. Main findings of the selected papers were
reported in the \emph{Table} below. The quality assessment, according to
the Newcastle-Ottawa Scale, showed an high risk of bias for all of them
(\emph{Appendice B} ). This might be due to the small size of the
cohorts selected for the studies.

\textbf{Discussion}

A preliminary study by Vidal \emph{et al.} reported transcutaneous NIRS
measurements in 24 children after KT {[}7{]}. Renal rSrO2 measured by
NIRS significantly increased over time during the first three days after
surgery and a significant correlation was found with serum creatinine,
estimated glomerular filtration rate (eGFR) and with the decrease of
post-operative urine-neutrophilgelatinase-associated lipocaine (u-NGAL),
which is a marker of tubular injury reflecting the ischemic and
reperfusion damage of the kidney. In this series, DUS did not identify
any abnormality in renal vascularisation and no vascular complications
were reported. To date, four patients experienced a delayed graft
function (DGF) without any peculiar modifications of rSO2.

Despite these promising results, Skowno \emph{et al.} raised some
criticisms {[}8{]}. First, DUS, the gold standard for the assessment of
allograft perfusion, was not related to rSrO2. Recently,
Malakasioti\emph{et al} . identified a significant correlation between
renal rSO2 measured by NIRS and resistive index derived from DUS in a
series of 29 paediatric patients {[}9{]}. Once again, no complications
were reported in the cohort.

Second, the region of interest of NIRS may reach up to 4 cm below the
skin, according to the manufacturers, and its effectiveness in
monitoring somatic perfusion was validated in infants weighing less than
10 kg {[}10{]}. This body weight was sensibly lower than those of the
patients undergone KT. However, Skowno \emph{et al.} confirmed the
effect of body size on transcutaneous NIRS only in a porcine model,
suggesting its \emph{in vivo} application up to 1 cm of depth {[}11{]}.

Nevertheless, Pérez Civantos \emph{et al.} assessed renal rSrO2 in 61
adults undergone KT, using probes with a maximum depth of 2.5 cm
{[}12{]}. NIRS readings were significantly correlated to the decreasing
values of serum lactate at eight hours and 24 hours, which is another
marker of ischemic injury. Furthermore, renal rSrO2 was related to
initial diuresis at three hours and to mixed central venous oxygen
saturation. On the other hand, no correlation with DUS was found. In
addition, in this series arterial thrombosis and bleedings were
encountered, showing a maintained decrease in rSrO2 which might
anticipate the vascular events. Moreover, the same study was replicated
in liver transplantations. Even in this scenario, NIRS decreased early
during bleeding or in case of thrombosis {[}13{]}.

The last concern about NIRS regarded the placement of the probes. The
vascularisation over the surgical wounds may be altered by the healing
process, Skowno \emph{et al.} speculated that a placement directly over
that area might influence NIRS readings {[}8{]}. Therefore, experimental
studies on reliable animal models, such as rats or piglets, should
better clarify the real impact of abdominal wall thickness and of the
healing process on transcutaneous NIRS monitoring.

Furthermore, the normal range of renal rSrO2 values need to be
established by investigating a larger number of patients. Only after
this process, NIRS might help in the prompt identification of acute
adverse events, which is the final aim of real-time NIRS monitoring. At
the moment, NIRS contributed to the early diagnosis of vascular
complications in two children undergone liver transplantation {[}15{]}.
However, even if renal rSrO2 was not altered among the patients affected
by DGF in the series by Vidal \emph{et al.} , the Authors suggested that
NIRS might help in discriminating the causes of oligo-anuria in the
early post-operative time after KT, helping in managing the
postoperative fluid balance {[}7{]}.

In conclusion, preliminary studies showed the correlation between NIRS,
graft function and graft perfusion in paediatric KTs. Further
investigation should also relate rSrO2 to perfusion renal scintigraphy,
which is the most objective modality to assess renal allograft
vascularisation and function {[}4{]}. Before large-scale \emph{in
vivo}utilisation, experimentation of NIRS on animal models might
investigate factors influencing the measurements of renal rSrO2, such as
the depth of the region of interest and the correct placement of the
probes. Furthermore, animal models or selected cohorts of patients might
help in defining the normal values of renal rSrO2.

\textbf{References}

1. Gulati A, Sarwal MM. Pediatric renal transplantation: an overview and
an update. \emph{Curr Opin Pediatr} 2010; 22(2):189-196.

2. Wang C, Greenbaum LA, Patzer RE, Garro R, Warshaw B, George RP et al.
Renal allograft loss due to renal vascular thrombosis in the US
pediatric renal transplantation. \emph{Pediatr Nephrol} 2019;
34(9):1545-1555. Monitoraggio DUS

3. Nixon JN, Biyyam DR, Stanescu L, Phillips GS, Finn LS, Parisi MT.
Imaging of pediatric renal transplants and their complications: a
pictorial review. \emph{Radiographics} 2013; 33(5):1227-51.

4. Baxter GM. Ultrasound of renal transplantation. \emph{Clin
Radiol}2001; 56(10):802-18.

5. Denault A, Ali MS, Couture EJ, Beaubien-Souligny, Bouabdallaoui N,
Brassard P et al. A Practical Approach to Cerebro-Somatic Near-Infrared
Spectroscopy and Whole-Body Ultrasound. \emph{J Cardiothorac Vasc
Anesth} 2019; 33 Suppl 1:S11-S37.

6. Kagaya Y, Miyamoto S. A systematic review of near-infrared
spectroscopy in flap monitoring: Current basic and clinical evidence and
prospects. \emph{J Plast Reconstr Aesthet Surg} 2018; 71(2):246-257.

7. Vidal E, Amigoni A, Brugnolaro V, Ghirardo G, Gamba P, Pettenazzo A
et al. Near-infrared spectroscopy as continuous real-time monitoring for
kidney graft perfusion. \emph{Pediatr Nephrol} 2014; 29:909-914.

8. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis
JPA et al. The PRISMA statement for reporting systematic reviews and
meta-analyses of studies that evaluate health care interventions:
explanation and elaboration. \emph{PLoS Med} 2009; 6(7):e1000100.

9. Skowno JJ, Karpelowsky JS. Near-infrared spectroscopy for monitoring
renal transplant perfusion. \emph{Pediatr Nephrol} 2014; 29:2241-2242.

10. Malakasioti G, Marks SD, Watson T, Williams F, Taylor-Allkins M,
Mamode N et al. Continuous monitoring of kidney transplant perfusion
with near-infrared spectroscopy. \emph{Nephrol Dial Transplant} 2018;
33:1863-1869.

11. Ortmann LA, Fontenot EE, Seib PM, Eble BK, Brown R, Bhutta AT. Use
of near-infrared spectroscopy for estimation of renal oxygenation in
children with heart disease. \emph{Pediatr Cardiol} 2011; 32:748-753.

12. Skowno JJ, Karpelowsky JS, Watts NR, Little DG. Can transcutaneous
near infrared spectroscopy detect severe hepatic ischemia: a juvenile
porcine model. \emph{Paediatr Anaesth} 2016; 26(12):1188-1196.

13. Pérez Civantos DV, Muñoz Cantero A, Robles Marcos M, Fariñas Seijas
H, Santiago Triviño MA, Pérez Frutos MD et al. Utility of Basal Regional
Oximetry Saturation for the Diagnosis of Acute Tubular Necrosis in the
Early Postoperative Period Following Kidney
Transplantation.\emph{Transplant Proc} 2019; 51(2):328-333.

14. Pérez Civantos DV, Muñoz Cantero A, Robles Marcos M, Fuentes
Morillas F, Cerezo Arias MO, Fariñas Seijas H. Utility of Basal Regional
Oximetry as an Early Predictor of Graft Failure After Liver
Transplant.\emph{Transplant Proc} 2019; 51(2):353-358.

15. Shiba J, Satoh M, Taira K, Niwa Y, Inoue S, Mizuta K et al.
Near-infrared spectroscopy might be a useful tool for predicting the
risk of vascular complications after paediatric liver transplants: Two
case reports. \emph{Pediatr Transplant} 2018; 22(1).

\emph{Table.} Clinical studies assessing the feasibility of real-time
NIRS monitoring of allograft perfusion.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Study}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Country}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Design}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Population}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Main Findings}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Vidal \emph{et al}., 2014 {[}7{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Italy\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Prospective\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
24 paediatric kidney transplants\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
rSrO2 correlated with serum creatinine, eGFR and u-NGAL.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Malakasioti \emph{et al}., 2018 {[}9{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
UK\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Prospective\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29 paediatric kidney transplants\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
rSrO2 correlated with resistive index by DUS and systolic blood
pressure.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Shiba \emph{et al}., 2018 {[}15{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Japan\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Case Report\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 paediatric liver transplants\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Decrease in rSrO2 anticipated vascular complications.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
P\selectlanguage{ngerman}érez Civantos \emph{et al}., 2019 {[}12{]}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Spain\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Prospective\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
61 adult kidney transplants\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Decrease in rSrO2 anticipated vascular complications. rSrO2 correlated
with serum lactate and initial diuresis.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
P\selectlanguage{ngerman}érez Civantos \emph{et al}., 2019 {[}13{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Spain\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Prospective\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
50 adult liver transplants\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Decrease in rSrO2 anticipated vascular complications.\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Appendices}

\emph{Appendice A.} Systematic Review according to the PRISMA
guidelines.

\emph{Appendice B.} Quality assessment of the selected articles
according to Newcastle-Ottawa Scale.\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllll@{}}
\toprule
\textbf{Study} & \textbf{Study design} & \textbf{Selection} &
\textbf{Selection} & \textbf{Selection} & \textbf{Selection} &
\textbf{Comparability} & \textbf{Comparability} &
\textbf{Exposure/Outcome} & \textbf{Exposure/Outcome} &
\textbf{Exposure/Outcome}\tabularnewline
& & \textbf{1} & \textbf{2} & \textbf{3} & \textbf{4} & \textbf{a} &
\textbf{b} & \textbf{1} & \textbf{2} & \textbf{3}\tabularnewline
Vidal \emph{et al}., 2014 {[}7{]} & Cohort & & & * & * & * & & * & &
*\tabularnewline
Malakasioti \emph{et al}., 2018 {[}9{]} & Cohort & & & * & * & * & & * &
& *\tabularnewline
Shiba \emph{et al}., 2018 {[}15{]} & Cohort & & & * & & * & & * & * &
*\tabularnewline
P\selectlanguage{ngerman}érez Civantos \emph{et al}., 2019 {[}12{]} & Cohort & & & * & * & * & *
& * & & *\tabularnewline
P\selectlanguage{ngerman}érez Civantos \emph{et al}., 2019 {[}13{]} & Cohort & & & * & * & * & *
& * & & *\tabularnewline
\bottomrule
\end{longtable}

\selectlanguage{english}
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