Continuous monitoring of kidney transplant perfusion with near-infrared spectroscopy

Continuous monitoring of kidney transplant perfusion with near-infrared spectroscopy Abstract Background Current reliance on clinical, laboratory and Doppler ultrasound (DUS) parameters for monitoring kidney transplant perfusion in the immediate post-operative period in children risks late recognition of allograft hypoperfusion and vascular complications. Near-infrared spectroscopy (NIRS) is a real-time, non-invasive technique for monitoring tissue oxygenation percutaneously. NIRS monitoring of kidney transplant perfusion has not previously been validated to the gold standard of DUS. We examined whether NIRS tissue oxygenation indices can reliably assess blood flow in established paediatric kidney transplants. Methods Paediatric kidney transplant recipients ages 1–18 years with stable allograft function were eligible. Participants underwent routine DUS assessment of kidney transplant perfusion, including resistive index (RI) and peak systolic velocity at the upper and lower poles. NIRS data [tissue oxygenation index (TOI%)] were recorded for a minimum of 2 min with NIRS sensors placed on the skin over upper and lower allograft poles. Results Twenty-nine subjects with a median age of 13.3 (range 4.8–17.8) years and a median transplant vintage of 26.5 months participated. Thirteen (45%) were female and 20 (69%) were living donor kidney recipients. NIRS monitoring was well tolerated by all, with 96–100% valid measurements. Significant negative correlations were observed between NIRS TOI% and DUS RI at both the upper and lower poles (r = −0.4 and −0.6, P = 0.04 and 0.001, respectively). Systolic blood pressure but not estimated glomerular filtration rate also correlated with NIRS TOI% (P = 0.01). Conclusions NIRS indices correlate well with DUS perfusion and haemodynamic parameters in established paediatric kidney transplant recipients. Further studies are warranted to extend NIRS use for continuous real-time monitoring of early post-transplant perfusion status. Doppler ultrasonography, kidney transplantation, near-infrared spectroscopy, paediatrics, perfusion, physiologic monitoring INTRODUCTION Kidney transplantation is the treatment of choice for end-stage kidney disease, offering improved overall health outcomes, quality of life and health economic benefits relative to dialysis [1–4]. Early transplant dysfunction can occur for multiple reasons [5, 6]. Thrombosis affects 4–18% of paediatric kidney transplants and is a significant cause of graft loss within the first year [7–10]. Children <6 years of age are particularly susceptible due to smaller vessel size and relatively lower cardiac output perfusing an adult kidney [11, 12]. Appropriate fluid and/or inotropic support is paramount in order to optimize transplant perfusion. Currently, clinical and laboratory parameters such as changes in serum creatinine and urine output are used to monitor graft perfusion, with Doppler ultrasound (DUS) performed if concerns arise. These parameters do not reflect changes in the transplanted organ’s perfusion in real time, which delays diagnosis of vascular complications. DUS is the gold standard method for assessing renal allograft blood flow [13–15]. Resistive index (RI) and peak systolic velocity (PSV) are the principal indices of organ vascular resistance related to microvascular injury and interstitial oedema and patency of larger transplant vessels [16–18]. A key limitation of DUS is that it does not allow continuous real-time monitoring of perfusion in the critical early post-transplantation period. Near-infrared spectroscopy (NIRS) is a non-invasive, continuous, real-time measure of tissue oxygenation [19]. Established applications include monitoring brain perfusion during cardiopulmonary bypass and global tissue perfusion in septic shock [20]. Renal NIRS was found to be an early predictor of acute kidney injury in infants with congenital heart disease undergoing surgical repair [21]. In animal models, testicular NIRS detected organ ischaemia earlier than DUS [22]. One previous study compared NIRS measurements in paediatric transplant recipients to plasma creatinine, urine output and urinary neutrophil gelatinase-associated lipocalin (NGAL), but not to DUS [23]. The aim of this pilot study was to assess whether NIRS can be used to assess renal allograft perfusion in stable paediatric recipients by comparing it with the current gold standard of DUS. MATERIALS AND METHODS Patient eligibility and assessment Paediatric kidney transplant recipients <18 years of age with stable allograft function at the Department of Paediatric Nephrology at Great Ormond Street Hospital were eligible. Exclusion criteria were (i) wound complications affecting skin overlying the transplant, (ii) anticipated patient’s inability to lie still for NIRS recording and (iii) intercurrent illness impacting fluid status or allograft function. Informed consent was obtained from participants and parents/caregivers as appropriate. The study was approved by a national research ethics committee and the Health Research Authority (ref: 16/LO/1897). Participants were assessed during routine transplant clinic. Assessment included a clinical history review to identify any acute intercurrent illness, physical examination for anthropometric data and blood pressure measurement, blood sampling for standard biochemistry (including plasma creatinine), estimated glomerular filtration rate (eGFR) calculation based on the Schwartz formula and renal allograft ultrasound with Doppler blood flow measurements [24]. Blood pressures were obtained manually with Doppler amplification as per recent guidelines [25]. Ultrasound imaging with colour flow Doppler Ultrasound transplant imaging was undertaken as part of routine annual or biannual surveillance by a single trained paediatric radiographer. The GE Logiq E9 ultrasound system with a curvilinear 1–5 MHz or linear array 5–9 MHz transducer was used for optimal signal penetration and resolution. Initial machine settings were according to the manufacturer’s recommendations (renal transplant preset) and adjustments were applied by the operator to the depth (magnification), focus, gain, dynamic range and Doppler scale (velocity range/colour gain). This was individual to each patient. The positions of transplant upper and lower poles were marked on the patient’s skin with a hypoallergenic marker. Images were reviewed by a paediatric radiologist. Measurements included peak systolic and diastolic velocities and resistive indices from both the main renal transplant artery and vein and from intrarenal vessels at the upper and lower poles. Upper and lower pole depths from the skin surface were recorded. Assessment of global and regional perfusion was made. NIRS measurements NIRS monitoring was undertaken using the NIRO 200-NX (Hamamatsu Photonics KK, Hamamatsu City, Japan). Relevant skin areas were cleaned with a chlorohexidine wipe and paediatric optodes were positioned over the upper and lower pole skin markings. External light penetration was minimized by securing an opaque adhesive membrane to the skin. NIRS measurements were recorded and displayed continuously from each pole from two separate channels for a minimum of 2 min with patients lying supine. Individual NIRS data were extracted from the NIRO 200-NX with an encrypted portable external memory disk and converted into an Excel (Microsoft, Redmond, WA, USA) document for statistical analysis. Outcome measures and data analysis The RI derived from DUS was the primary outcome and the tissue oxygenation index (TOI%) was the main explanatory variable. The mean TOI% at each pole was used for analyses, as acute changes in allograft perfusion were not anticipated. The relationship between TOI% (upper and lower pole) and RI (upper and lower pole, respectively) was evaluated using linear regression. As the distance of the tissue of interest from the infrared light source might affect NIRS measurements, the interaction between pole depth and TOI% was also examined. To further clarify the physiological significance of TOI%, its correlation with systolic blood pressure and eGFR was evaluated, as these parameters were previously reported to be associated with NIRS [23, 26, 27]. Continuous variables are expressed as mean ±standard deviation (SD) if normally distributed, otherwise as median (range). Analyses were performed using SPSS Statistics for Windows, version 21.0 (IBM, Armonk, NY, USA). ETHICAL APPROVAL All procedures performed were in accordance with the 1964 Helsinki Declaration ethical standards and its later amendments. The study was approved by a national research ethics committee and the Health Research Authority (ref: 16/LO/1897) RESULTS Patients’ characteristics Twenty-nine patients with a median age of 13.3 (range 4.8–17.8) years participated. Patients’ demographic characteristics, underlying diagnoses, transplant operation details and allograft function at the time of the study are summarized in Table 1. Table 1. Subject characteristics Age (years), median (range) 13.3 (4.8–17.8) Female, n (%) 13 (44.8) Time post-transplant (months), median (range) 26.5 (1–48.7) Diagnoses, n (%)  CAKUT 15 (51.7)  Ciliopathies 4 (13.8)  Cystic kidney disease 3 (10.3)  Inborn errors of metabolism 3 (10.3)  Congenital nephrotic syndrome 2 (6.9)  Other 2 (6.9) Type of transplant, n (%)  Living donor 20 (69)  Extraperitoneal surgical approach 19 (65.5) Systolic BP (mmHg), mean ± SD 102.9 ± 11.5 [median 102 (IQR 98–112)] eGFR (mL/min/1.73 m2), mean ± SD 52.5 ± 19.9 Age (years), median (range) 13.3 (4.8–17.8) Female, n (%) 13 (44.8) Time post-transplant (months), median (range) 26.5 (1–48.7) Diagnoses, n (%)  CAKUT 15 (51.7)  Ciliopathies 4 (13.8)  Cystic kidney disease 3 (10.3)  Inborn errors of metabolism 3 (10.3)  Congenital nephrotic syndrome 2 (6.9)  Other 2 (6.9) Type of transplant, n (%)  Living donor 20 (69)  Extraperitoneal surgical approach 19 (65.5) Systolic BP (mmHg), mean ± SD 102.9 ± 11.5 [median 102 (IQR 98–112)] eGFR (mL/min/1.73 m2), mean ± SD 52.5 ± 19.9 BP, blood pressure; CAKUT, congenital anomalies of kidneys and urinary tract; IQR, interquartile range. Table 1. Subject characteristics Age (years), median (range) 13.3 (4.8–17.8) Female, n (%) 13 (44.8) Time post-transplant (months), median (range) 26.5 (1–48.7) Diagnoses, n (%)  CAKUT 15 (51.7)  Ciliopathies 4 (13.8)  Cystic kidney disease 3 (10.3)  Inborn errors of metabolism 3 (10.3)  Congenital nephrotic syndrome 2 (6.9)  Other 2 (6.9) Type of transplant, n (%)  Living donor 20 (69)  Extraperitoneal surgical approach 19 (65.5) Systolic BP (mmHg), mean ± SD 102.9 ± 11.5 [median 102 (IQR 98–112)] eGFR (mL/min/1.73 m2), mean ± SD 52.5 ± 19.9 Age (years), median (range) 13.3 (4.8–17.8) Female, n (%) 13 (44.8) Time post-transplant (months), median (range) 26.5 (1–48.7) Diagnoses, n (%)  CAKUT 15 (51.7)  Ciliopathies 4 (13.8)  Cystic kidney disease 3 (10.3)  Inborn errors of metabolism 3 (10.3)  Congenital nephrotic syndrome 2 (6.9)  Other 2 (6.9) Type of transplant, n (%)  Living donor 20 (69)  Extraperitoneal surgical approach 19 (65.5) Systolic BP (mmHg), mean ± SD 102.9 ± 11.5 [median 102 (IQR 98–112)] eGFR (mL/min/1.73 m2), mean ± SD 52.5 ± 19.9 BP, blood pressure; CAKUT, congenital anomalies of kidneys and urinary tract; IQR, interquartile range. DUS measurements Twenty-nine kidney transplant ultrasound studies with colour flow Doppler for perfusion assessment were undertaken. No patients demonstrated significant urinary tract obstruction, perinephric collection or other acute surgical complications. All had patent transplant renal vessels without evidence of stenosis based on colour Doppler waveforms. Global allograft perfusion was normal in all recipients. PSVs, RIs and distances from the skin surface for the upper and lower graft poles are shown in Table 2. Table 2. DUS and NIRS summary data PSV (cm/s) RI Depth (cm) TOI % Upper pole 27.6 ± 7.8 0.65 ± 0.07 2.6 ± 1.2 78.8 ± 7.0 Lower pole 25.3 ± 8.0 0.65 ± 0.07 2.0 ± 0.9 79.3 ± 10.7 P-value NS NS 0.001 NS PSV (cm/s) RI Depth (cm) TOI % Upper pole 27.6 ± 7.8 0.65 ± 0.07 2.6 ± 1.2 78.8 ± 7.0 Lower pole 25.3 ± 8.0 0.65 ± 0.07 2.0 ± 0.9 79.3 ± 10.7 P-value NS NS 0.001 NS Values are expressed as mean ± SD. Table 2. DUS and NIRS summary data PSV (cm/s) RI Depth (cm) TOI % Upper pole 27.6 ± 7.8 0.65 ± 0.07 2.6 ± 1.2 78.8 ± 7.0 Lower pole 25.3 ± 8.0 0.65 ± 0.07 2.0 ± 0.9 79.3 ± 10.7 P-value NS NS 0.001 NS PSV (cm/s) RI Depth (cm) TOI % Upper pole 27.6 ± 7.8 0.65 ± 0.07 2.6 ± 1.2 78.8 ± 7.0 Lower pole 25.3 ± 8.0 0.65 ± 0.07 2.0 ± 0.9 79.3 ± 10.7 P-value NS NS 0.001 NS Values are expressed as mean ± SD. NIRS measurements A median of 838 NIRS readings per patient (range 384–2860) were obtained. NIRS monitoring was well tolerated by all participants, with a 96–100% rate of valid measurements. Summary statistics for TOI% values (upper and lower pole) are provided in Table 2. TOI% as a predictor of DUS-derived RI The TOI% in the lower and upper poles was significantly associated with the respective RIs (r = −0.60, P = 0.001; and r = −0.40, P = 0.04) (Figures 1 and 2). FIGURE 1 View largeDownload slide Correlation between NIRS TOI% and DUS RI at the lower pole (r = −0.60, P = 0.001). FIGURE 1 View largeDownload slide Correlation between NIRS TOI% and DUS RI at the lower pole (r = −0.60, P = 0.001). FIGURE 2 View largeDownload slide Correlation between NIRS TOI% and DUS RI at the upper pole (r = −0.40, P = 0.04). FIGURE 2 View largeDownload slide Correlation between NIRS TOI% and DUS RI at the upper pole (r = −0.40, P = 0.04). Univariate linear regression yielded the following prediction equations for the lower and upper pole RIs: RI lower pole = 0.941 + [−0.004 × (TOI% lower pole)] RI upper pole = 0.972 + [−0.004 × (TOI% upper pole)] There was no interaction between (lower or upper) pole depth and (lower or upper) TOI% (P = 0.24 and P = 0.29, respectively). TOI% and association with other parameters Both the upper pole and lower pole TOI% were significantly associated with systolic blood pressure but not with eGFR (Table 3). Table 3. Correlation of TOI% with systolic BP and eGFR TOI%, upper pole TOI%, lower pole Other variables r P-value r P-value eGFR −0.24 0.22 −0.30 0.11 Systolic BP 0.50 <0.01 0.45 0.01 TOI%, upper pole TOI%, lower pole Other variables r P-value r P-value eGFR −0.24 0.22 −0.30 0.11 Systolic BP 0.50 <0.01 0.45 0.01 BP, blood pressure. Table 3. Correlation of TOI% with systolic BP and eGFR TOI%, upper pole TOI%, lower pole Other variables r P-value r P-value eGFR −0.24 0.22 −0.30 0.11 Systolic BP 0.50 <0.01 0.45 0.01 TOI%, upper pole TOI%, lower pole Other variables r P-value r P-value eGFR −0.24 0.22 −0.30 0.11 Systolic BP 0.50 <0.01 0.45 0.01 BP, blood pressure. DISCUSSION This study demonstrates the feasibility of using NIRS to monitor kidney transplant perfusion in paediatric recipients. A significant correlation was observed between real-time NIRS TOI% and RI derived from the gold standard clinical measure of perfusion, DUS. Moreover, TOI% correlated with systolic blood pressure, a classic haemodynamic parameter related to allograft perfusion. The physiological principle underlying NIRS is that detection of a change in the spectrum of infrared light reflected from a tissue bed is dependent on the relative concentration of oxygenated and deoxygenated haemoglobin [20]. The use of NIRS in perioperative and critical care has grown in recent years; the real-time continuous nature of monitoring and its ability to predict hypoxia-induced tissue damage in shocked patients earlier than gold standards of global perfusion such as blood pressure, lactate and the venous saturation of oxygen are considered its major advantages [21, 28]. Renal oxygen saturation was a reliable predictor of hypoxia-induced adverse outcomes, including acute kidney injury following cardiac surgery, and was demonstrated to be a superior marker of acute renal hypoperfusion than plasma creatinine, eGFR and urinary NGAL [21, 29]. A decrease in renal oximetry perioperatively or in states of shock is thought to reflect the shift of blood flow to the vital organs at the expense of kidney perfusion [28]. DUS is considered the gold standard tool for assessing renal allograft perfusion; RI is an index of organ vascular compliance and correlates with eGFR in the early post-transplantation period and with long-term allograft survival [13, 18, 30, 31]. In this cohort of stable paediatric kidney transplant recipients, RI values were within the normal range reported in adult studies and no vascular complications were detected on DUS [18]. An inverse relationship between NIRS TOI% and RI measurements was observed. This observation is physiologically plausible, as an increased RI represents higher vascular resistance that negatively impacts perfusion and organ oxygenation. These data corroborate previous observations in limb blood flow with agreement between NIRS and DUS [32]. Vidal et al. [23] demonstrated that renal oximetry (NIRS) parameters tended to improve over the initial 3 days following transplantation, as a result of ongoing vascular remodelling, and correlated with graft function. The present study demonstrates that renal oximetry is associated with sonographic markers of perfusion under stable conditions. The utility of renal oximetry as a tool to monitor transplant kidney perfusion is reinforced by our observation that TOI% is directly correlated with systolic blood pressure, a traditional haemodynamic parameter. This suggests that NIRS could differentiate primary graft dysfunction caused by problems in organ perfusion in real-time arising either from surgical vascular complications (transplant renal vein or artery thrombosis), suboptimal circulatory volume or systemic blood pressure and thus kidney perfusion pressure. Paediatric kidney transplantation poses fluid management dilemmas. When an adult kidney is transplanted into a small recipient, large volumes of intravenous fluid and inotropes are used to ensure allograft perfusion, both of which can result in adverse effects if not implemented judiciously [11]. Moreover, fluid management strategies are decided on clinical and biochemical indices of fluid status that are neither sensitive nor specific enough to recognize hypovolaemia or organ hypoperfusion [33]. The diversity among various institutional post-operative fluid management protocols reflects these difficulties. Application of real-time perfusion monitoring with NIRS has the potential to overcome these challenges in the post-operative period. Decisions on the rate of intravenous fluid administration and inotrope use, currently based solely on clinical assessment, could be assisted by utilization of changes in NIRS parameters. A further potential application of NIRS in the early post-transplantation period is estimation of oxygen adequacy at a microvascular level. The sensitivity of DUS to detect cortical blood flow beyond arcuate vessels is limited, which impairs detection of early renal venous thrombosis and intrarenal vessel involvement [34, 35]. Moreover, DUS-derived RI is confounded by processes causing interstitial oedema in the transplant, such as rejection or acute tubular necrosis [36]. Renal oximetry values in children with delayed graft function are similar to those from recipients with good function, supporting the value of NIRS in differentiating perfusion-related causes of graft dysfunction [23]. Moreover, in experimental studies on rat kidneys, occlusion of the renal artery and vein resulted in a significant decline in renal oxygen saturation within a few seconds, with earlier detection than with clinical, laboratory or DUS assessment [37, 38]. No study to date has evaluated normal renal NIRS values in renal transplant recipients. Intraindividual variability is a key limitation of this technique, underlying the importance of trend monitoring rather than isolated absolute measurements [21, 39]. Renal NIRS TOI% values observed in our cohort are in accordance with values quoted from studies on native kidneys and from children in the early post-transplant period. Somatic NIRS values obtained from native kidneys are higher than cerebral by 10–20% and it has been suggested that a 20% decrease from baseline represents clinically significant hypoperfusion. This has led some investigators to propose that NIRS could be used in post operative patients to guide fluid management decisions. In a study that evaluated NIRS use in neonates after digestive surgeries, tailoring of the fluid management strategy based on NIRS measurements led to improved renal oximetry values, with the conclusion that regional renal oximetry reflects global perfusion status [40]. NIRS tissue oxygen saturation has previously been reported to be affected by the distance of the organ of interest from the skin [41]. Some investigators have proposed a maximum depth of 8 cm for use of this modality [28]. In the current study, despite differing depths of the sampling sites from the skin, no significant difference in TOI% between the upper and lower poles of the transplant was observed. Furthermore, the effect of the interaction between TOI% and the poles’ distance from the skin was not significant. This supports the feasibility of NIRS monitoring across patients of different age, body habitus and surgical approach for allograft placement. When we conducted our analysis separately for patients with either intra- or extraperitoneally placed organs there was no difference in the allografts’ pole distance from the skin or in the TOI%. This observation is particularly important for the youngest recipients, who are more likely to have an intraperitoneally placed kidney. It is also noteworthy that measurements of renal oximetry from two different graft sites in our group of established paediatric renal transplant recipients are seemingly reproducible. Reproducibility of NIRS measurements can be enhanced with the use of two different channels for monitoring [42]. In our study, we used two pairs of optodes (one for each graft pole) under a steady perfusion state. TOI% recordings were similar between the two poles in organs with homogeneity in perfusion according to DUS. Our study is limited primarily by the small number of participants. Its observational nature did not allow validation of the NIRS response versus DUS in situations where fluctuations in renal allograft perfusion take place. In the absence of NIRS normative data, the inherent method limitations in obtaining such and the importance of trend monitoring perioperatively, it becomes clear that renal oximetry needs further validation before it can be implemented in paediatric kidney transplantation. In order to validate our findings, a future observational trial where NIRS monitoring would start in the recovery area outside the operating room might be useful. It is common clinical practice that renal allograft perfusion is assessed immediately postoperatively with DUS. At this point, paediatric kidney recipients might have received up to 190 mL/kg intravenous fluid volume and potentially inotropes to maintain central venous pressure and optimal organ perfusion [43]. NIRS indices at this point of optimized perfusion could be used as baseline values for the individual recipient–graft pair. Owens et al. [33] found that acute kidney injury in infants after cardiac surgery was predicted by a sustained decrease in renal oximetry values of >50% from baseline over 2 h. While this might be an excessive and unacceptably prolonged decline in the setting of kidney transplantation, previous studies have highlighted the importance of trend monitoring [21, 40]. It has been suggested that a 20–25% decline in renal oximetry was an AKI predictor in paediatric cardiac surgery and could prompt fluid resuscitation in neonates following digestive surgery [21, 40]. In order to establish which deviation from the baseline NIRS value obtained in the recovery room is clinically significant, data from NIRS recordings obtained over a 24-h period post-transplant could be incorporated into a receiver operating characteristics analysis aimed at assessing the depth and duration of renal tissue hypoxia that could best predict adverse outcomes in blood pressure, urine output and eGFR. Also, the impact of interventions such as administration of fluid boluses, diuretics and inotropes on NIRS parameters should be recorded and correlated to the respective changes in haemodynamic indices and allograft function. In summary, the current pilot study demonstrates the feasibility and tolerability of NIRS measurements in paediatric kidney transplantation. Real-time NIRS parameters correlate with DUS and systolic blood pressure as traditional measures of allograft perfusion. The depth of the transplant does not appear to influence NIRS accuracy. Further trials are warranted to examine the utility of NIRS for early recognition of microvascular events and to guide immediate decisions on fluid and inotrope management at the bedside in paediatric kidney transplant recipients. ACKNOWLEDGEMENTS This project was supported by the National Institute for Health Research (NiHR) Biomedical Research Centres based at Guy's and St Thomas National Health Service (NHS) Foundation Trust and King's College London as well as Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. The views expressed are those of the authors and not necessarily those of the NHS, the NiHR of the Department of Health. AUTHORS’ CONTRIBUTIONS G.M., S.D.M., N.M., J.M. and W.N.H. designed the study. G.M., F.W., M.T-A. and T.W. collected the data. G.M. analysed the data. G.M. drafted and W.N.H. edited the manuscript. The results presented have not been published previously in whole or part, except in abstract form. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Czyzewski L , Sanko RJ , Wyzgal J et al. Assessment of health-related quality of life of patients after kidney transplantation in comparison with hemodialysis and peritoneal dialysis . Ann Transplant 2014 ; 19 : 576 – 585 Google Scholar CrossRef Search ADS PubMed 2 Gillen DL , Stehman-Breen CO , Smith JM et al. Survival advantage of pediatric recipients of a first kidney transplant among children awaiting kidney transplantation . Am J Transplant 2008 ; 8 : 2600 – 2606 Google Scholar CrossRef Search ADS PubMed 3 Abecassis M , Bartlett ST , Collins AJ et al. Kidney transplantation as primary therapy for end-stage renal disease: a National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/KDOQITM) conference . Clin J Am Soc Nephrol 2008 ; 3 : 471 – 480 Google Scholar CrossRef Search ADS PubMed 4 Liem YS , Weimar W. Early living-donor kidney transplantation: a review of the associated survival benefit . Transplantation 2009 ; 87 : 317 – 318 Google Scholar CrossRef Search ADS PubMed 5 Lim EC , Terasaki PI. Early graft function . Clin Transpl 1991 ; 401 – 407 6 Irish WD , McCollum DA , Tesi RJ et al. Nomogram for predicting the likelihood of delayed graft function in adult cadaveric renal transplant recipients . J Am Soc Nephrol 2003 ; 14 : 2967 – 2974 Google Scholar CrossRef Search ADS PubMed 7 Rodricks N , Chanchlani R , Banh T et al. Incidence and risk factors of early surgical complications in young renal transplant recipients: a persistent challenge . Pediatr Transplantation 2017 ; 21 : e13006 . Google Scholar CrossRef Search ADS 8 van Lieburg AF , de Jong MCJW , Hoitsma AJ et al. Renal transplant thrombosis in children . J Pediatr Surg 1995 ; 30 : 615 – 619 Google Scholar CrossRef Search ADS PubMed 9 Ponticelli C , Moia M , Montagnino G. Renal allograft thrombosis . Nephrol Dial Transplant 2009 ; 24 : 1388 – 1393 Google Scholar CrossRef Search ADS PubMed 10 Smith JM , Stablein D , Singh A et al. Decreased risk of renal allograft thrombosis associated with interleukin-2 receptor antagonists: a report of the NAPRTCS . Am J Transplant 2006 ; 6 : 585 – 588 Google Scholar CrossRef Search ADS PubMed 11 Taylor K , Kim WT , Maharramova M et al. Intraoperative management and early postoperative outcomes of pediatric renal transplants . Paediatr Anaesth 2016 ; 26 : 987 – 991 Google Scholar CrossRef Search ADS PubMed 12 Vitola SP , Gnatta D , Garcia VD et al. Kidney transplantation in children weighing less than 15 kg: extraperitoneal surgical access—experience with 62 cases . Pediatr Transplantation 2013 ; 17 : 445 – 453 Google Scholar CrossRef Search ADS 13 Meyer M , Paushter D , Steinmuller DR. The use of duplex Doppler ultrasonography to evaluate renal allograft dysfunction . Transplantation 1990 ; 50 : 974 – 978 Google Scholar CrossRef Search ADS PubMed 14 Schwenger V , Hinkel UP , Nahm AM et al. Color Doppler ultrasonography in the diagnostic evaluation of renal allografts . Nephron Clin Pract 2006 ; 104 : c107 – c112 Google Scholar CrossRef Search ADS PubMed 15 Jimenez C , Lopez MO , Gonzalez E et al. Ultrasonography in kidney transplantation: values and new developments . Transplant Rev 2009 ; 23 : 209 – 213 Google Scholar CrossRef Search ADS 16 Chudek J , Kolonko A , Krol R et al. The intrarenal vascular resistance parameters measured by duplex Doppler ultrasound shortly after kidney transplantation in patients with immediate, slow, and delayed graft function . Transplant Proc 2006 ; 38 : 42 – 45 Google Scholar CrossRef Search ADS PubMed 17 Ardalan MR , Tarzamani MK , Shoja MM. A correlation between direct and indirect Doppler ultrasonographic measures in transplant renal artery stenosis . Transplant Proc 2007 ; 39 : 1436 – 1438 Google Scholar CrossRef Search ADS PubMed 18 Nezami N , Tarzamni MK , Argani H et al. Doppler ultrasonographic indices after renal transplantation as renal function predictors . Transplant Proc 2008 ; 40 : 94 – 99 Google Scholar CrossRef Search ADS PubMed 19 Jobsis FF. Noninvasive, infrared monitoring of cerebral and myocardial oxygen sufficiency and circulatory parameters . Science 1977 ; 198 : 1264 – 1267 Google Scholar CrossRef Search ADS PubMed 20 Chakravarti S , Srivastava S , Mittnacht AJ. Near infrared spectroscopy (NIRS) in children . Semin Cardiothorac Vasc Anesth 2008 ; 12 : 70 – 79 Google Scholar CrossRef Search ADS PubMed 21 Ruf B , Bonelli V , Balling G et al. Intraoperative renal near-infrared spectroscopy indicates developing acute kidney injury in infants undergoing cardiac surgery with cardiopulmonary bypass: a case-control study . Crit Care 2015 ; 19 : 27 Google Scholar CrossRef Search ADS PubMed 22 Aydogdu O , Burgu B , Gocun PU et al. Near infrared spectroscopy to diagnose experimental testicular torsion: comparison with Doppler ultrasound and immunohistochemical correlation of tissue oxygenation and viability . J Urol 2012 ; 187 : 744 – 750 Google Scholar CrossRef Search ADS PubMed 23 Vidal E , Amigoni A , Brugnolaro V et al. Near-infrared spectroscopy as continuous real-time monitoring for kidney graft perfusion . Pediatr Nephrol 2014 ; 29 : 909 – 914 Google Scholar CrossRef Search ADS PubMed 24 Schwartz GJ , Munoz A , Schneider MF et al. New equations to estimate GFR in children with CKD . J Am Soc Nephrol 2009 ; 20 : 629 – 637 Google Scholar CrossRef Search ADS PubMed 25 Flynn JT , Kaelber DC , Baker-Smith CM et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents . Pediatrics 2017 ; 140 : e20171904 Google Scholar CrossRef Search ADS PubMed 26 Georger JF , Hamzaoui O , Chaari A et al. Restoring arterial pressure with norepinephrine improves muscle tissue oxygenation assessed by near-infrared spectroscopy in severely hypotensive septic patients . Intensive Care Med 2010 ; 36 : 1882 – 1889 Google Scholar CrossRef Search ADS PubMed 27 Cohn SM , Nathens AB , Moore FA et al. Tissue oxygen saturation predicts the development of organ dysfunction during traumatic shock resuscitation . J Trauma 2007 ; 62 : 44 – 54 , discussion 54–45 Google Scholar CrossRef Search ADS PubMed 28 Epstein CD , Haghenbeck KT. Bedside assessment of tissue oxygen saturation monitoring in critically ill adults: an integrative review of the literature . Crit Care Res Pract 2014 ; 2014 : 709683 Google Scholar PubMed 29 Gist KM , Kaufman J , da Cruz EM et al. A decline in intraoperative renal near-infrared spectroscopy is associated with adverse outcomes in children following cardiac surgery . Pediatr Crit Care Med 2016 ; 17 : 342 – 349 Google Scholar CrossRef Search ADS PubMed 30 Meier M , Fricke L , Eikenbusch K et al. The serial duplex index improves differential diagnosis of acute renal transplant dysfunction . J Ultrasound Med 2017 ; 36 : 1607 – 1615 Google Scholar CrossRef Search ADS PubMed 31 Melek E , Baskin E , Gulleroglu K et al. The predictive value of resistive index obtained by doppler ultrasonography early after renal transplantation on long-term allograft function . Pediatr Transplant 2017 ; 21 : e12860 Google Scholar CrossRef Search ADS 32 Ives SJ , Fadel PJ , Brothers RM et al. Exploring the vascular smooth muscle receptor landscape in vivo: ultrasound Doppler versus near-infrared spectroscopy assessments . Am J Physiol Heart Circ Physiol 2014 ; 306 : H771 – H776 Google Scholar CrossRef Search ADS PubMed 33 Owens GE , King K , Gurney JG et al. Low renal oximetry correlates with acute kidney injury after infant cardiac surgery . Pediatr Cardiol 2011 ; 32 : 183 – 188 Google Scholar CrossRef Search ADS PubMed 34 Aschwanden M , Thalhammer C , Schaub S et al. Renal vein thrombosis after renal transplantation—early diagnosis by duplex sonography prevented fatal outcome . Nephrol Dial Transplant 2006 ; 21 : 825 – 826 Google Scholar CrossRef Search ADS PubMed 35 Trillaud H , Merville P , Tran Le Linh P et al. Color Doppler sonography in early renal transplantation follow-up: resistive index measurements versus power Doppler sonography . AJR Am J Roentgenol 1998 ; 171 : 1611 – 1615 Google Scholar CrossRef Search ADS PubMed 36 Datta R , Sandhu M , Saxena AK et al. Role of duplex Doppler and power Doppler sonography in transplanted kidneys with acute renal parenchymal dysfunction . Australas Radiol 2005 ; 49 : 15 – 20 Google Scholar CrossRef Search ADS PubMed 37 Grosenick D , Cantow K , Arakelyan K et al. Detailing renal hemodynamics and oxygenation in rats by a combined near-infrared spectroscopy and invasive probe approach . Biomed Opt Express 2015 ; 6 : 309 – 323 Google Scholar CrossRef Search ADS PubMed 38 Shadgan B , Macnab A , Nigro M et al. Optical monitoring of kidney oxygenation and hemodynamics using a miniaturized near-infrared sensor. Proc SPIE, Therapeutics and Diagnostics in Urology: Lasers, Robotics, Minimally Invasive, and Advanced Biomedical Devices. Abstract 10038 39 Hyttel-Sorensen S , Sorensen LC , Riera J et al. Tissue oximetry: a comparison of mean values of regional tissue saturation, reproducibility and dynamic range of four NIRS-instruments on the human forearm . Biomed Opt Express 2011 ; 2 : 3047 – 3057 Google Scholar CrossRef Search ADS PubMed 40 Beck J , Loron G , Masson C et al. Monitoring cerebral and renal oxygenation status during neonatal digestive surgeries using near infrared spectroscopy . Front Pediatr 2017 ; 5 : 140 Google Scholar CrossRef Search ADS PubMed 41 Ortmann LA , Fontenot EE , Seib PM et al. Use of near-infrared spectroscopy for estimation of renal oxygenation in children with heart disease . Pediatr Cardiol 2011 ; 32 : 748 – 753 Google Scholar CrossRef Search ADS PubMed 42 Hyttel-Sorensen S , Sorensen LC , Riera J et al. Tissue oximetry: a comparison of mean values of regional tissue saturation, reproducibility and dynamic range of four NIRS-instruments on the human forearm . Biomed Optics Express 2011 ; 2 : 3047 – 3057 Google Scholar CrossRef Search ADS 43 Coupe N , O’Brien M , Gibson P et al. Anesthesia for pediatric renal transplantation with and without epidural analgesia–a review of 7 years experience . Paediatr Anaesth 2005 ; 15 : 220 – 228 Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Continuous monitoring of kidney transplant perfusion with near-infrared spectroscopy

Loading next page...
 
/lp/ou_press/continuous-monitoring-of-kidney-transplant-perfusion-with-near-CP7Gx94W6p
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
ISSN
0931-0509
eISSN
1460-2385
D.O.I.
10.1093/ndt/gfy116
Publisher site
See Article on Publisher Site

Abstract

Abstract Background Current reliance on clinical, laboratory and Doppler ultrasound (DUS) parameters for monitoring kidney transplant perfusion in the immediate post-operative period in children risks late recognition of allograft hypoperfusion and vascular complications. Near-infrared spectroscopy (NIRS) is a real-time, non-invasive technique for monitoring tissue oxygenation percutaneously. NIRS monitoring of kidney transplant perfusion has not previously been validated to the gold standard of DUS. We examined whether NIRS tissue oxygenation indices can reliably assess blood flow in established paediatric kidney transplants. Methods Paediatric kidney transplant recipients ages 1–18 years with stable allograft function were eligible. Participants underwent routine DUS assessment of kidney transplant perfusion, including resistive index (RI) and peak systolic velocity at the upper and lower poles. NIRS data [tissue oxygenation index (TOI%)] were recorded for a minimum of 2 min with NIRS sensors placed on the skin over upper and lower allograft poles. Results Twenty-nine subjects with a median age of 13.3 (range 4.8–17.8) years and a median transplant vintage of 26.5 months participated. Thirteen (45%) were female and 20 (69%) were living donor kidney recipients. NIRS monitoring was well tolerated by all, with 96–100% valid measurements. Significant negative correlations were observed between NIRS TOI% and DUS RI at both the upper and lower poles (r = −0.4 and −0.6, P = 0.04 and 0.001, respectively). Systolic blood pressure but not estimated glomerular filtration rate also correlated with NIRS TOI% (P = 0.01). Conclusions NIRS indices correlate well with DUS perfusion and haemodynamic parameters in established paediatric kidney transplant recipients. Further studies are warranted to extend NIRS use for continuous real-time monitoring of early post-transplant perfusion status. Doppler ultrasonography, kidney transplantation, near-infrared spectroscopy, paediatrics, perfusion, physiologic monitoring INTRODUCTION Kidney transplantation is the treatment of choice for end-stage kidney disease, offering improved overall health outcomes, quality of life and health economic benefits relative to dialysis [1–4]. Early transplant dysfunction can occur for multiple reasons [5, 6]. Thrombosis affects 4–18% of paediatric kidney transplants and is a significant cause of graft loss within the first year [7–10]. Children <6 years of age are particularly susceptible due to smaller vessel size and relatively lower cardiac output perfusing an adult kidney [11, 12]. Appropriate fluid and/or inotropic support is paramount in order to optimize transplant perfusion. Currently, clinical and laboratory parameters such as changes in serum creatinine and urine output are used to monitor graft perfusion, with Doppler ultrasound (DUS) performed if concerns arise. These parameters do not reflect changes in the transplanted organ’s perfusion in real time, which delays diagnosis of vascular complications. DUS is the gold standard method for assessing renal allograft blood flow [13–15]. Resistive index (RI) and peak systolic velocity (PSV) are the principal indices of organ vascular resistance related to microvascular injury and interstitial oedema and patency of larger transplant vessels [16–18]. A key limitation of DUS is that it does not allow continuous real-time monitoring of perfusion in the critical early post-transplantation period. Near-infrared spectroscopy (NIRS) is a non-invasive, continuous, real-time measure of tissue oxygenation [19]. Established applications include monitoring brain perfusion during cardiopulmonary bypass and global tissue perfusion in septic shock [20]. Renal NIRS was found to be an early predictor of acute kidney injury in infants with congenital heart disease undergoing surgical repair [21]. In animal models, testicular NIRS detected organ ischaemia earlier than DUS [22]. One previous study compared NIRS measurements in paediatric transplant recipients to plasma creatinine, urine output and urinary neutrophil gelatinase-associated lipocalin (NGAL), but not to DUS [23]. The aim of this pilot study was to assess whether NIRS can be used to assess renal allograft perfusion in stable paediatric recipients by comparing it with the current gold standard of DUS. MATERIALS AND METHODS Patient eligibility and assessment Paediatric kidney transplant recipients <18 years of age with stable allograft function at the Department of Paediatric Nephrology at Great Ormond Street Hospital were eligible. Exclusion criteria were (i) wound complications affecting skin overlying the transplant, (ii) anticipated patient’s inability to lie still for NIRS recording and (iii) intercurrent illness impacting fluid status or allograft function. Informed consent was obtained from participants and parents/caregivers as appropriate. The study was approved by a national research ethics committee and the Health Research Authority (ref: 16/LO/1897). Participants were assessed during routine transplant clinic. Assessment included a clinical history review to identify any acute intercurrent illness, physical examination for anthropometric data and blood pressure measurement, blood sampling for standard biochemistry (including plasma creatinine), estimated glomerular filtration rate (eGFR) calculation based on the Schwartz formula and renal allograft ultrasound with Doppler blood flow measurements [24]. Blood pressures were obtained manually with Doppler amplification as per recent guidelines [25]. Ultrasound imaging with colour flow Doppler Ultrasound transplant imaging was undertaken as part of routine annual or biannual surveillance by a single trained paediatric radiographer. The GE Logiq E9 ultrasound system with a curvilinear 1–5 MHz or linear array 5–9 MHz transducer was used for optimal signal penetration and resolution. Initial machine settings were according to the manufacturer’s recommendations (renal transplant preset) and adjustments were applied by the operator to the depth (magnification), focus, gain, dynamic range and Doppler scale (velocity range/colour gain). This was individual to each patient. The positions of transplant upper and lower poles were marked on the patient’s skin with a hypoallergenic marker. Images were reviewed by a paediatric radiologist. Measurements included peak systolic and diastolic velocities and resistive indices from both the main renal transplant artery and vein and from intrarenal vessels at the upper and lower poles. Upper and lower pole depths from the skin surface were recorded. Assessment of global and regional perfusion was made. NIRS measurements NIRS monitoring was undertaken using the NIRO 200-NX (Hamamatsu Photonics KK, Hamamatsu City, Japan). Relevant skin areas were cleaned with a chlorohexidine wipe and paediatric optodes were positioned over the upper and lower pole skin markings. External light penetration was minimized by securing an opaque adhesive membrane to the skin. NIRS measurements were recorded and displayed continuously from each pole from two separate channels for a minimum of 2 min with patients lying supine. Individual NIRS data were extracted from the NIRO 200-NX with an encrypted portable external memory disk and converted into an Excel (Microsoft, Redmond, WA, USA) document for statistical analysis. Outcome measures and data analysis The RI derived from DUS was the primary outcome and the tissue oxygenation index (TOI%) was the main explanatory variable. The mean TOI% at each pole was used for analyses, as acute changes in allograft perfusion were not anticipated. The relationship between TOI% (upper and lower pole) and RI (upper and lower pole, respectively) was evaluated using linear regression. As the distance of the tissue of interest from the infrared light source might affect NIRS measurements, the interaction between pole depth and TOI% was also examined. To further clarify the physiological significance of TOI%, its correlation with systolic blood pressure and eGFR was evaluated, as these parameters were previously reported to be associated with NIRS [23, 26, 27]. Continuous variables are expressed as mean ±standard deviation (SD) if normally distributed, otherwise as median (range). Analyses were performed using SPSS Statistics for Windows, version 21.0 (IBM, Armonk, NY, USA). ETHICAL APPROVAL All procedures performed were in accordance with the 1964 Helsinki Declaration ethical standards and its later amendments. The study was approved by a national research ethics committee and the Health Research Authority (ref: 16/LO/1897) RESULTS Patients’ characteristics Twenty-nine patients with a median age of 13.3 (range 4.8–17.8) years participated. Patients’ demographic characteristics, underlying diagnoses, transplant operation details and allograft function at the time of the study are summarized in Table 1. Table 1. Subject characteristics Age (years), median (range) 13.3 (4.8–17.8) Female, n (%) 13 (44.8) Time post-transplant (months), median (range) 26.5 (1–48.7) Diagnoses, n (%)  CAKUT 15 (51.7)  Ciliopathies 4 (13.8)  Cystic kidney disease 3 (10.3)  Inborn errors of metabolism 3 (10.3)  Congenital nephrotic syndrome 2 (6.9)  Other 2 (6.9) Type of transplant, n (%)  Living donor 20 (69)  Extraperitoneal surgical approach 19 (65.5) Systolic BP (mmHg), mean ± SD 102.9 ± 11.5 [median 102 (IQR 98–112)] eGFR (mL/min/1.73 m2), mean ± SD 52.5 ± 19.9 Age (years), median (range) 13.3 (4.8–17.8) Female, n (%) 13 (44.8) Time post-transplant (months), median (range) 26.5 (1–48.7) Diagnoses, n (%)  CAKUT 15 (51.7)  Ciliopathies 4 (13.8)  Cystic kidney disease 3 (10.3)  Inborn errors of metabolism 3 (10.3)  Congenital nephrotic syndrome 2 (6.9)  Other 2 (6.9) Type of transplant, n (%)  Living donor 20 (69)  Extraperitoneal surgical approach 19 (65.5) Systolic BP (mmHg), mean ± SD 102.9 ± 11.5 [median 102 (IQR 98–112)] eGFR (mL/min/1.73 m2), mean ± SD 52.5 ± 19.9 BP, blood pressure; CAKUT, congenital anomalies of kidneys and urinary tract; IQR, interquartile range. Table 1. Subject characteristics Age (years), median (range) 13.3 (4.8–17.8) Female, n (%) 13 (44.8) Time post-transplant (months), median (range) 26.5 (1–48.7) Diagnoses, n (%)  CAKUT 15 (51.7)  Ciliopathies 4 (13.8)  Cystic kidney disease 3 (10.3)  Inborn errors of metabolism 3 (10.3)  Congenital nephrotic syndrome 2 (6.9)  Other 2 (6.9) Type of transplant, n (%)  Living donor 20 (69)  Extraperitoneal surgical approach 19 (65.5) Systolic BP (mmHg), mean ± SD 102.9 ± 11.5 [median 102 (IQR 98–112)] eGFR (mL/min/1.73 m2), mean ± SD 52.5 ± 19.9 Age (years), median (range) 13.3 (4.8–17.8) Female, n (%) 13 (44.8) Time post-transplant (months), median (range) 26.5 (1–48.7) Diagnoses, n (%)  CAKUT 15 (51.7)  Ciliopathies 4 (13.8)  Cystic kidney disease 3 (10.3)  Inborn errors of metabolism 3 (10.3)  Congenital nephrotic syndrome 2 (6.9)  Other 2 (6.9) Type of transplant, n (%)  Living donor 20 (69)  Extraperitoneal surgical approach 19 (65.5) Systolic BP (mmHg), mean ± SD 102.9 ± 11.5 [median 102 (IQR 98–112)] eGFR (mL/min/1.73 m2), mean ± SD 52.5 ± 19.9 BP, blood pressure; CAKUT, congenital anomalies of kidneys and urinary tract; IQR, interquartile range. DUS measurements Twenty-nine kidney transplant ultrasound studies with colour flow Doppler for perfusion assessment were undertaken. No patients demonstrated significant urinary tract obstruction, perinephric collection or other acute surgical complications. All had patent transplant renal vessels without evidence of stenosis based on colour Doppler waveforms. Global allograft perfusion was normal in all recipients. PSVs, RIs and distances from the skin surface for the upper and lower graft poles are shown in Table 2. Table 2. DUS and NIRS summary data PSV (cm/s) RI Depth (cm) TOI % Upper pole 27.6 ± 7.8 0.65 ± 0.07 2.6 ± 1.2 78.8 ± 7.0 Lower pole 25.3 ± 8.0 0.65 ± 0.07 2.0 ± 0.9 79.3 ± 10.7 P-value NS NS 0.001 NS PSV (cm/s) RI Depth (cm) TOI % Upper pole 27.6 ± 7.8 0.65 ± 0.07 2.6 ± 1.2 78.8 ± 7.0 Lower pole 25.3 ± 8.0 0.65 ± 0.07 2.0 ± 0.9 79.3 ± 10.7 P-value NS NS 0.001 NS Values are expressed as mean ± SD. Table 2. DUS and NIRS summary data PSV (cm/s) RI Depth (cm) TOI % Upper pole 27.6 ± 7.8 0.65 ± 0.07 2.6 ± 1.2 78.8 ± 7.0 Lower pole 25.3 ± 8.0 0.65 ± 0.07 2.0 ± 0.9 79.3 ± 10.7 P-value NS NS 0.001 NS PSV (cm/s) RI Depth (cm) TOI % Upper pole 27.6 ± 7.8 0.65 ± 0.07 2.6 ± 1.2 78.8 ± 7.0 Lower pole 25.3 ± 8.0 0.65 ± 0.07 2.0 ± 0.9 79.3 ± 10.7 P-value NS NS 0.001 NS Values are expressed as mean ± SD. NIRS measurements A median of 838 NIRS readings per patient (range 384–2860) were obtained. NIRS monitoring was well tolerated by all participants, with a 96–100% rate of valid measurements. Summary statistics for TOI% values (upper and lower pole) are provided in Table 2. TOI% as a predictor of DUS-derived RI The TOI% in the lower and upper poles was significantly associated with the respective RIs (r = −0.60, P = 0.001; and r = −0.40, P = 0.04) (Figures 1 and 2). FIGURE 1 View largeDownload slide Correlation between NIRS TOI% and DUS RI at the lower pole (r = −0.60, P = 0.001). FIGURE 1 View largeDownload slide Correlation between NIRS TOI% and DUS RI at the lower pole (r = −0.60, P = 0.001). FIGURE 2 View largeDownload slide Correlation between NIRS TOI% and DUS RI at the upper pole (r = −0.40, P = 0.04). FIGURE 2 View largeDownload slide Correlation between NIRS TOI% and DUS RI at the upper pole (r = −0.40, P = 0.04). Univariate linear regression yielded the following prediction equations for the lower and upper pole RIs: RI lower pole = 0.941 + [−0.004 × (TOI% lower pole)] RI upper pole = 0.972 + [−0.004 × (TOI% upper pole)] There was no interaction between (lower or upper) pole depth and (lower or upper) TOI% (P = 0.24 and P = 0.29, respectively). TOI% and association with other parameters Both the upper pole and lower pole TOI% were significantly associated with systolic blood pressure but not with eGFR (Table 3). Table 3. Correlation of TOI% with systolic BP and eGFR TOI%, upper pole TOI%, lower pole Other variables r P-value r P-value eGFR −0.24 0.22 −0.30 0.11 Systolic BP 0.50 <0.01 0.45 0.01 TOI%, upper pole TOI%, lower pole Other variables r P-value r P-value eGFR −0.24 0.22 −0.30 0.11 Systolic BP 0.50 <0.01 0.45 0.01 BP, blood pressure. Table 3. Correlation of TOI% with systolic BP and eGFR TOI%, upper pole TOI%, lower pole Other variables r P-value r P-value eGFR −0.24 0.22 −0.30 0.11 Systolic BP 0.50 <0.01 0.45 0.01 TOI%, upper pole TOI%, lower pole Other variables r P-value r P-value eGFR −0.24 0.22 −0.30 0.11 Systolic BP 0.50 <0.01 0.45 0.01 BP, blood pressure. DISCUSSION This study demonstrates the feasibility of using NIRS to monitor kidney transplant perfusion in paediatric recipients. A significant correlation was observed between real-time NIRS TOI% and RI derived from the gold standard clinical measure of perfusion, DUS. Moreover, TOI% correlated with systolic blood pressure, a classic haemodynamic parameter related to allograft perfusion. The physiological principle underlying NIRS is that detection of a change in the spectrum of infrared light reflected from a tissue bed is dependent on the relative concentration of oxygenated and deoxygenated haemoglobin [20]. The use of NIRS in perioperative and critical care has grown in recent years; the real-time continuous nature of monitoring and its ability to predict hypoxia-induced tissue damage in shocked patients earlier than gold standards of global perfusion such as blood pressure, lactate and the venous saturation of oxygen are considered its major advantages [21, 28]. Renal oxygen saturation was a reliable predictor of hypoxia-induced adverse outcomes, including acute kidney injury following cardiac surgery, and was demonstrated to be a superior marker of acute renal hypoperfusion than plasma creatinine, eGFR and urinary NGAL [21, 29]. A decrease in renal oximetry perioperatively or in states of shock is thought to reflect the shift of blood flow to the vital organs at the expense of kidney perfusion [28]. DUS is considered the gold standard tool for assessing renal allograft perfusion; RI is an index of organ vascular compliance and correlates with eGFR in the early post-transplantation period and with long-term allograft survival [13, 18, 30, 31]. In this cohort of stable paediatric kidney transplant recipients, RI values were within the normal range reported in adult studies and no vascular complications were detected on DUS [18]. An inverse relationship between NIRS TOI% and RI measurements was observed. This observation is physiologically plausible, as an increased RI represents higher vascular resistance that negatively impacts perfusion and organ oxygenation. These data corroborate previous observations in limb blood flow with agreement between NIRS and DUS [32]. Vidal et al. [23] demonstrated that renal oximetry (NIRS) parameters tended to improve over the initial 3 days following transplantation, as a result of ongoing vascular remodelling, and correlated with graft function. The present study demonstrates that renal oximetry is associated with sonographic markers of perfusion under stable conditions. The utility of renal oximetry as a tool to monitor transplant kidney perfusion is reinforced by our observation that TOI% is directly correlated with systolic blood pressure, a traditional haemodynamic parameter. This suggests that NIRS could differentiate primary graft dysfunction caused by problems in organ perfusion in real-time arising either from surgical vascular complications (transplant renal vein or artery thrombosis), suboptimal circulatory volume or systemic blood pressure and thus kidney perfusion pressure. Paediatric kidney transplantation poses fluid management dilemmas. When an adult kidney is transplanted into a small recipient, large volumes of intravenous fluid and inotropes are used to ensure allograft perfusion, both of which can result in adverse effects if not implemented judiciously [11]. Moreover, fluid management strategies are decided on clinical and biochemical indices of fluid status that are neither sensitive nor specific enough to recognize hypovolaemia or organ hypoperfusion [33]. The diversity among various institutional post-operative fluid management protocols reflects these difficulties. Application of real-time perfusion monitoring with NIRS has the potential to overcome these challenges in the post-operative period. Decisions on the rate of intravenous fluid administration and inotrope use, currently based solely on clinical assessment, could be assisted by utilization of changes in NIRS parameters. A further potential application of NIRS in the early post-transplantation period is estimation of oxygen adequacy at a microvascular level. The sensitivity of DUS to detect cortical blood flow beyond arcuate vessels is limited, which impairs detection of early renal venous thrombosis and intrarenal vessel involvement [34, 35]. Moreover, DUS-derived RI is confounded by processes causing interstitial oedema in the transplant, such as rejection or acute tubular necrosis [36]. Renal oximetry values in children with delayed graft function are similar to those from recipients with good function, supporting the value of NIRS in differentiating perfusion-related causes of graft dysfunction [23]. Moreover, in experimental studies on rat kidneys, occlusion of the renal artery and vein resulted in a significant decline in renal oxygen saturation within a few seconds, with earlier detection than with clinical, laboratory or DUS assessment [37, 38]. No study to date has evaluated normal renal NIRS values in renal transplant recipients. Intraindividual variability is a key limitation of this technique, underlying the importance of trend monitoring rather than isolated absolute measurements [21, 39]. Renal NIRS TOI% values observed in our cohort are in accordance with values quoted from studies on native kidneys and from children in the early post-transplant period. Somatic NIRS values obtained from native kidneys are higher than cerebral by 10–20% and it has been suggested that a 20% decrease from baseline represents clinically significant hypoperfusion. This has led some investigators to propose that NIRS could be used in post operative patients to guide fluid management decisions. In a study that evaluated NIRS use in neonates after digestive surgeries, tailoring of the fluid management strategy based on NIRS measurements led to improved renal oximetry values, with the conclusion that regional renal oximetry reflects global perfusion status [40]. NIRS tissue oxygen saturation has previously been reported to be affected by the distance of the organ of interest from the skin [41]. Some investigators have proposed a maximum depth of 8 cm for use of this modality [28]. In the current study, despite differing depths of the sampling sites from the skin, no significant difference in TOI% between the upper and lower poles of the transplant was observed. Furthermore, the effect of the interaction between TOI% and the poles’ distance from the skin was not significant. This supports the feasibility of NIRS monitoring across patients of different age, body habitus and surgical approach for allograft placement. When we conducted our analysis separately for patients with either intra- or extraperitoneally placed organs there was no difference in the allografts’ pole distance from the skin or in the TOI%. This observation is particularly important for the youngest recipients, who are more likely to have an intraperitoneally placed kidney. It is also noteworthy that measurements of renal oximetry from two different graft sites in our group of established paediatric renal transplant recipients are seemingly reproducible. Reproducibility of NIRS measurements can be enhanced with the use of two different channels for monitoring [42]. In our study, we used two pairs of optodes (one for each graft pole) under a steady perfusion state. TOI% recordings were similar between the two poles in organs with homogeneity in perfusion according to DUS. Our study is limited primarily by the small number of participants. Its observational nature did not allow validation of the NIRS response versus DUS in situations where fluctuations in renal allograft perfusion take place. In the absence of NIRS normative data, the inherent method limitations in obtaining such and the importance of trend monitoring perioperatively, it becomes clear that renal oximetry needs further validation before it can be implemented in paediatric kidney transplantation. In order to validate our findings, a future observational trial where NIRS monitoring would start in the recovery area outside the operating room might be useful. It is common clinical practice that renal allograft perfusion is assessed immediately postoperatively with DUS. At this point, paediatric kidney recipients might have received up to 190 mL/kg intravenous fluid volume and potentially inotropes to maintain central venous pressure and optimal organ perfusion [43]. NIRS indices at this point of optimized perfusion could be used as baseline values for the individual recipient–graft pair. Owens et al. [33] found that acute kidney injury in infants after cardiac surgery was predicted by a sustained decrease in renal oximetry values of >50% from baseline over 2 h. While this might be an excessive and unacceptably prolonged decline in the setting of kidney transplantation, previous studies have highlighted the importance of trend monitoring [21, 40]. It has been suggested that a 20–25% decline in renal oximetry was an AKI predictor in paediatric cardiac surgery and could prompt fluid resuscitation in neonates following digestive surgery [21, 40]. In order to establish which deviation from the baseline NIRS value obtained in the recovery room is clinically significant, data from NIRS recordings obtained over a 24-h period post-transplant could be incorporated into a receiver operating characteristics analysis aimed at assessing the depth and duration of renal tissue hypoxia that could best predict adverse outcomes in blood pressure, urine output and eGFR. Also, the impact of interventions such as administration of fluid boluses, diuretics and inotropes on NIRS parameters should be recorded and correlated to the respective changes in haemodynamic indices and allograft function. In summary, the current pilot study demonstrates the feasibility and tolerability of NIRS measurements in paediatric kidney transplantation. Real-time NIRS parameters correlate with DUS and systolic blood pressure as traditional measures of allograft perfusion. The depth of the transplant does not appear to influence NIRS accuracy. Further trials are warranted to examine the utility of NIRS for early recognition of microvascular events and to guide immediate decisions on fluid and inotrope management at the bedside in paediatric kidney transplant recipients. ACKNOWLEDGEMENTS This project was supported by the National Institute for Health Research (NiHR) Biomedical Research Centres based at Guy's and St Thomas National Health Service (NHS) Foundation Trust and King's College London as well as Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. The views expressed are those of the authors and not necessarily those of the NHS, the NiHR of the Department of Health. AUTHORS’ CONTRIBUTIONS G.M., S.D.M., N.M., J.M. and W.N.H. designed the study. G.M., F.W., M.T-A. and T.W. collected the data. G.M. analysed the data. G.M. drafted and W.N.H. edited the manuscript. The results presented have not been published previously in whole or part, except in abstract form. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Czyzewski L , Sanko RJ , Wyzgal J et al. Assessment of health-related quality of life of patients after kidney transplantation in comparison with hemodialysis and peritoneal dialysis . Ann Transplant 2014 ; 19 : 576 – 585 Google Scholar CrossRef Search ADS PubMed 2 Gillen DL , Stehman-Breen CO , Smith JM et al. Survival advantage of pediatric recipients of a first kidney transplant among children awaiting kidney transplantation . Am J Transplant 2008 ; 8 : 2600 – 2606 Google Scholar CrossRef Search ADS PubMed 3 Abecassis M , Bartlett ST , Collins AJ et al. Kidney transplantation as primary therapy for end-stage renal disease: a National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/KDOQITM) conference . Clin J Am Soc Nephrol 2008 ; 3 : 471 – 480 Google Scholar CrossRef Search ADS PubMed 4 Liem YS , Weimar W. Early living-donor kidney transplantation: a review of the associated survival benefit . Transplantation 2009 ; 87 : 317 – 318 Google Scholar CrossRef Search ADS PubMed 5 Lim EC , Terasaki PI. Early graft function . Clin Transpl 1991 ; 401 – 407 6 Irish WD , McCollum DA , Tesi RJ et al. Nomogram for predicting the likelihood of delayed graft function in adult cadaveric renal transplant recipients . J Am Soc Nephrol 2003 ; 14 : 2967 – 2974 Google Scholar CrossRef Search ADS PubMed 7 Rodricks N , Chanchlani R , Banh T et al. Incidence and risk factors of early surgical complications in young renal transplant recipients: a persistent challenge . Pediatr Transplantation 2017 ; 21 : e13006 . Google Scholar CrossRef Search ADS 8 van Lieburg AF , de Jong MCJW , Hoitsma AJ et al. Renal transplant thrombosis in children . J Pediatr Surg 1995 ; 30 : 615 – 619 Google Scholar CrossRef Search ADS PubMed 9 Ponticelli C , Moia M , Montagnino G. Renal allograft thrombosis . Nephrol Dial Transplant 2009 ; 24 : 1388 – 1393 Google Scholar CrossRef Search ADS PubMed 10 Smith JM , Stablein D , Singh A et al. Decreased risk of renal allograft thrombosis associated with interleukin-2 receptor antagonists: a report of the NAPRTCS . Am J Transplant 2006 ; 6 : 585 – 588 Google Scholar CrossRef Search ADS PubMed 11 Taylor K , Kim WT , Maharramova M et al. Intraoperative management and early postoperative outcomes of pediatric renal transplants . Paediatr Anaesth 2016 ; 26 : 987 – 991 Google Scholar CrossRef Search ADS PubMed 12 Vitola SP , Gnatta D , Garcia VD et al. Kidney transplantation in children weighing less than 15 kg: extraperitoneal surgical access—experience with 62 cases . Pediatr Transplantation 2013 ; 17 : 445 – 453 Google Scholar CrossRef Search ADS 13 Meyer M , Paushter D , Steinmuller DR. The use of duplex Doppler ultrasonography to evaluate renal allograft dysfunction . Transplantation 1990 ; 50 : 974 – 978 Google Scholar CrossRef Search ADS PubMed 14 Schwenger V , Hinkel UP , Nahm AM et al. Color Doppler ultrasonography in the diagnostic evaluation of renal allografts . Nephron Clin Pract 2006 ; 104 : c107 – c112 Google Scholar CrossRef Search ADS PubMed 15 Jimenez C , Lopez MO , Gonzalez E et al. Ultrasonography in kidney transplantation: values and new developments . Transplant Rev 2009 ; 23 : 209 – 213 Google Scholar CrossRef Search ADS 16 Chudek J , Kolonko A , Krol R et al. The intrarenal vascular resistance parameters measured by duplex Doppler ultrasound shortly after kidney transplantation in patients with immediate, slow, and delayed graft function . Transplant Proc 2006 ; 38 : 42 – 45 Google Scholar CrossRef Search ADS PubMed 17 Ardalan MR , Tarzamani MK , Shoja MM. A correlation between direct and indirect Doppler ultrasonographic measures in transplant renal artery stenosis . Transplant Proc 2007 ; 39 : 1436 – 1438 Google Scholar CrossRef Search ADS PubMed 18 Nezami N , Tarzamni MK , Argani H et al. Doppler ultrasonographic indices after renal transplantation as renal function predictors . Transplant Proc 2008 ; 40 : 94 – 99 Google Scholar CrossRef Search ADS PubMed 19 Jobsis FF. Noninvasive, infrared monitoring of cerebral and myocardial oxygen sufficiency and circulatory parameters . Science 1977 ; 198 : 1264 – 1267 Google Scholar CrossRef Search ADS PubMed 20 Chakravarti S , Srivastava S , Mittnacht AJ. Near infrared spectroscopy (NIRS) in children . Semin Cardiothorac Vasc Anesth 2008 ; 12 : 70 – 79 Google Scholar CrossRef Search ADS PubMed 21 Ruf B , Bonelli V , Balling G et al. Intraoperative renal near-infrared spectroscopy indicates developing acute kidney injury in infants undergoing cardiac surgery with cardiopulmonary bypass: a case-control study . Crit Care 2015 ; 19 : 27 Google Scholar CrossRef Search ADS PubMed 22 Aydogdu O , Burgu B , Gocun PU et al. Near infrared spectroscopy to diagnose experimental testicular torsion: comparison with Doppler ultrasound and immunohistochemical correlation of tissue oxygenation and viability . J Urol 2012 ; 187 : 744 – 750 Google Scholar CrossRef Search ADS PubMed 23 Vidal E , Amigoni A , Brugnolaro V et al. Near-infrared spectroscopy as continuous real-time monitoring for kidney graft perfusion . Pediatr Nephrol 2014 ; 29 : 909 – 914 Google Scholar CrossRef Search ADS PubMed 24 Schwartz GJ , Munoz A , Schneider MF et al. New equations to estimate GFR in children with CKD . J Am Soc Nephrol 2009 ; 20 : 629 – 637 Google Scholar CrossRef Search ADS PubMed 25 Flynn JT , Kaelber DC , Baker-Smith CM et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents . Pediatrics 2017 ; 140 : e20171904 Google Scholar CrossRef Search ADS PubMed 26 Georger JF , Hamzaoui O , Chaari A et al. Restoring arterial pressure with norepinephrine improves muscle tissue oxygenation assessed by near-infrared spectroscopy in severely hypotensive septic patients . Intensive Care Med 2010 ; 36 : 1882 – 1889 Google Scholar CrossRef Search ADS PubMed 27 Cohn SM , Nathens AB , Moore FA et al. Tissue oxygen saturation predicts the development of organ dysfunction during traumatic shock resuscitation . J Trauma 2007 ; 62 : 44 – 54 , discussion 54–45 Google Scholar CrossRef Search ADS PubMed 28 Epstein CD , Haghenbeck KT. Bedside assessment of tissue oxygen saturation monitoring in critically ill adults: an integrative review of the literature . Crit Care Res Pract 2014 ; 2014 : 709683 Google Scholar PubMed 29 Gist KM , Kaufman J , da Cruz EM et al. A decline in intraoperative renal near-infrared spectroscopy is associated with adverse outcomes in children following cardiac surgery . Pediatr Crit Care Med 2016 ; 17 : 342 – 349 Google Scholar CrossRef Search ADS PubMed 30 Meier M , Fricke L , Eikenbusch K et al. The serial duplex index improves differential diagnosis of acute renal transplant dysfunction . J Ultrasound Med 2017 ; 36 : 1607 – 1615 Google Scholar CrossRef Search ADS PubMed 31 Melek E , Baskin E , Gulleroglu K et al. The predictive value of resistive index obtained by doppler ultrasonography early after renal transplantation on long-term allograft function . Pediatr Transplant 2017 ; 21 : e12860 Google Scholar CrossRef Search ADS 32 Ives SJ , Fadel PJ , Brothers RM et al. Exploring the vascular smooth muscle receptor landscape in vivo: ultrasound Doppler versus near-infrared spectroscopy assessments . Am J Physiol Heart Circ Physiol 2014 ; 306 : H771 – H776 Google Scholar CrossRef Search ADS PubMed 33 Owens GE , King K , Gurney JG et al. Low renal oximetry correlates with acute kidney injury after infant cardiac surgery . Pediatr Cardiol 2011 ; 32 : 183 – 188 Google Scholar CrossRef Search ADS PubMed 34 Aschwanden M , Thalhammer C , Schaub S et al. Renal vein thrombosis after renal transplantation—early diagnosis by duplex sonography prevented fatal outcome . Nephrol Dial Transplant 2006 ; 21 : 825 – 826 Google Scholar CrossRef Search ADS PubMed 35 Trillaud H , Merville P , Tran Le Linh P et al. Color Doppler sonography in early renal transplantation follow-up: resistive index measurements versus power Doppler sonography . AJR Am J Roentgenol 1998 ; 171 : 1611 – 1615 Google Scholar CrossRef Search ADS PubMed 36 Datta R , Sandhu M , Saxena AK et al. Role of duplex Doppler and power Doppler sonography in transplanted kidneys with acute renal parenchymal dysfunction . Australas Radiol 2005 ; 49 : 15 – 20 Google Scholar CrossRef Search ADS PubMed 37 Grosenick D , Cantow K , Arakelyan K et al. Detailing renal hemodynamics and oxygenation in rats by a combined near-infrared spectroscopy and invasive probe approach . Biomed Opt Express 2015 ; 6 : 309 – 323 Google Scholar CrossRef Search ADS PubMed 38 Shadgan B , Macnab A , Nigro M et al. Optical monitoring of kidney oxygenation and hemodynamics using a miniaturized near-infrared sensor. Proc SPIE, Therapeutics and Diagnostics in Urology: Lasers, Robotics, Minimally Invasive, and Advanced Biomedical Devices. Abstract 10038 39 Hyttel-Sorensen S , Sorensen LC , Riera J et al. Tissue oximetry: a comparison of mean values of regional tissue saturation, reproducibility and dynamic range of four NIRS-instruments on the human forearm . Biomed Opt Express 2011 ; 2 : 3047 – 3057 Google Scholar CrossRef Search ADS PubMed 40 Beck J , Loron G , Masson C et al. Monitoring cerebral and renal oxygenation status during neonatal digestive surgeries using near infrared spectroscopy . Front Pediatr 2017 ; 5 : 140 Google Scholar CrossRef Search ADS PubMed 41 Ortmann LA , Fontenot EE , Seib PM et al. Use of near-infrared spectroscopy for estimation of renal oxygenation in children with heart disease . Pediatr Cardiol 2011 ; 32 : 748 – 753 Google Scholar CrossRef Search ADS PubMed 42 Hyttel-Sorensen S , Sorensen LC , Riera J et al. Tissue oximetry: a comparison of mean values of regional tissue saturation, reproducibility and dynamic range of four NIRS-instruments on the human forearm . Biomed Optics Express 2011 ; 2 : 3047 – 3057 Google Scholar CrossRef Search ADS 43 Coupe N , O’Brien M , Gibson P et al. Anesthesia for pediatric renal transplantation with and without epidural analgesia–a review of 7 years experience . Paediatr Anaesth 2005 ; 15 : 220 – 228 Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Nephrology Dialysis TransplantationOxford University Press

Published: May 11, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off