Doppler ultrasound for the evaluation of chronic renal allograft dysfunction

Introduction

Chronic kidney disease (CKD) is a condition characterized by chronic structural changes and kidney dysfunction. It has multiple etiologies (1), and represents a significant health burden worldwide (2). Approximately 10% of adults worldwide are affected by CKD, resulting in 1.2 million deaths per year (3). In terminal cases of CKD, dialysis or kidney transplantation is necessary, with the latter being preferred when feasible (4). However, various complications may also occur after kidney transplantation.

Chronic renal allograft dysfunction (CRAD) is a common cause of late graft failure following kidney transplantation (5). It is defined as hypoperfusion of the transplanted kidney lasting at least 3 months, and its clinical symptoms include the progressive worsening of proteinuria and a gradual increase in serum creatinine (SCr) (6). CRAD is essentially a chronic rejection reaction, and its pathological changes include tubular atrophy (TA), interstitial fibrosis (IF), glomerulosclerosis or atrophy, basement membrane thickening, and narrowing of the small renal arteries (7). Puncture biopsy is the “gold standard” for the diagnosis of CRAD (8), and it is often performed when patients present with a rapid decline in transplanted kidney function, such as a persistent postoperative increase in SCr, a decrease of at least 20% in the estimated glomerular filtration rate (eGFR) from the baseline, or unexplained proteinuria (9). However, it can easily lead to various complications. Therefore, non-invasive methods to diagnose and quantify the degree of CRAD need to be established (10).

The existing diagnostic models for CRAD primarily rely on laboratory indicators or imaging techniques. Laboratory models, dependent on parameters like SCr, the eGFR, and cystatin-c (Cys-C), often lack specificity, and their predictive power can vary across populations due to racial and individual differences (11). Imaging modalities such as diffusion-weighted magnetic resonance imaging (DW-MRI) provide detailed information and have shown superior diagnostic efficacy for acute rejection compared to laboratory indicators alone (12,13). However, the high cost of DW-MRI limits its utility in routine follow-up (14). Consequently, diagnostic approaches relying solely on either laboratory or imaging data may yield suboptimal specificity.

Doppler ultrasound, valued for its convenience and real-time capabilities, is a primary imaging method for assessing kidney transplant dysfunction (15). Numerous studies have explored the role of various Doppler parameters in transplant kidney diseases, such as the peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistance index (RI), which is calculated as follows: RI = (PSV – EDV)/PSV (16). However, their reported conclusions regarding outcomes like delayed graft function (17,18) and acute rejection (19,20) are often inconsistent. To date, no clear consensus on effective Doppler ultrasound parametric indicators for diagnosing chronic allograft lesions has been reached.

Thus, we systematically collected ultrasound Doppler parameters from all levels of branch arteries in transplanted kidneys to investigate their diagnostic value for CRAD and their potential correlation with the severity of pathological changes. We present this article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1573/rc).

Methods

Patient selection

This retrospective study was registered with the Clinical Trials Center (ClinicalTrials.gov number, ChiCTR2000031370). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee on Biomedical Research, West China Hospital, Sichuan University (No. 2022453), and the requirement of individual consent for this retrospective analysis was waived.

Transplanted kidney recipients who underwent ultrasound examination at West China Hospital, Sichuan University between January 2011 and December 2021 were included in the study. Data on the pathologic diagnoses of the patients who underwent pathologic puncture were collected, and those who met the diagnostic criteria for CRAD were allocated to the CRAD group. The CRAD group was further subdivided into group I (mild CRAD) and group II (moderate-to-severe CRAD) based on the degree of pathological changes. The patients in the control group were randomly selected at a ratio of 1:1 based on the year of examination.

The inclusion criteria for the CRAD group were as follows: (I) time since transplantation >3 months; (II) pathological findings demonstrating chronic pathological changes, such as chronic antibody-mediated rejection (CAMR), chronic T-cell mediated rejection and non-specific IF/TA manifestations (21,22); and (III) an interval between the biopsy and Doppler ultrasound examination of ≤7 days. The inclusion criteria for the control group were as follows: (I) time since transplantation >3 months; (II) SCr and eGFR showing no significant abnormalities (23); (III) no other transplanted kidney-related complications such as transplant renal artery stenosis or transplanted renal vein thrombosis; and (IV) no significant abnormalities in the Doppler ultrasound examination results. The exclusion criteria were as follows: (I) unclear pathological diagnosis; (II) incomplete ultrasound data; and/or (III) poor ultrasound image quality such as no angle correction and non-standard measurement sections.

Based on the above criteria, a total of 12,107 transplant kidney ultrasounds were performed between 2011 and 2022. Additionally, 5,538 transplant kidney biopsy punctures were performed, including 122 cases with a pathologic diagnosis consistent with CRAD; however, a number of cases were excluded for the following reasons: no ultrasound performed within one week before and after the biopsy (n=20); incomplete ultrasound data (n=5); transplant renal artery stenosis and transplanted renal vein thrombosis (n=2); and substandard ultrasound image quality (n=3). Thus, ultimately, 92 patients were included in the CRAD group. A sample of 96 control patients was obtained by random selection at a ratio of 1:1 based on the year of examination (Figure 1).

Figure 1 Patient enrollment flow chart. CBCS, combined Banff chronicity score; CRAD, chronic renal allograft dysfunction; eGFR, estimated glomerular filtration rate; SCr, serum creatinine.

Ultrasound examination

The Doppler ultrasound blood flow parameters of the transplanted kidneys were obtained using an ultrasound imaging system. The ultrasound examination was performed using an ultrasound machine with a 1–6-MHz (SC6-1) convex-array transducer and a 9–13-MHz (SC13-9) linear-array transducer. All the examinations were performed by experienced radiologists and with the patient in the supine position. The measurements were taken while the patient was holding their breath. On the grayscale ultrasound examination, the length, width, and thickness of the kidney, echogenicity, size of the vertebra, and presence of hydronephrosis, stone, or tumor in renal allografts were evaluated. On the Doppler ultrasound examination, the tilt direction of the sampling box was parallel to the direction of vessel travel, and the angle of spectral Doppler measurement was <60° (24). The PSV, EDV, and RI of the renal artery, segmental artery, interlobar artery, and arcuate artery of the transplanted kidney were measured at least three times, and the average value was then recorded (Figure 2). The images were assessed by two specialized ultrasonographers, and images with satisfactory quality were deemed valid. The qualifying criteria included: clear visualization of the transplanted kidney edges, renal pelvis, and renal pyramid; a sample box of the transplanted renal blood flow parallel to the direction of the blood vessel being measured; and an angle of the measurement for the flow parameter of <60° from the direction of the blood vessel.

Figure 2 Doppler ultrasonography of transplanted kidneys. (A) Grayscale ultrasound of a transplanted kidney. (B) Color Doppler of blood flow of a transplanted kidney. (C) The PSV, EDV and RI of the renal artery. (D) The PSV, EDV and RI of the segmental artery. (E) The PSV, EDV and RI of the interlobar artery. (F) The PSV, EDV and RI of the arcuate artery. EDV, end-diastolic velocity; PSV, peak systolic velocity; RI, resistance index.

Transplantation renal pathology

All the specimens were reviewed by two pathologists with more than five years of experience. The chronic pathology of the biopsy tissues was graded according to the updated Banff classification. Glomerular double contours (cg, 0–3), IF (ci, 0–3), TA (ct, 0–3), vascular fibrous intimal thickening (cv, 0–3), and a combined Banff chronicity score (CBCS), which was calculated as follows: CBCS=ci + ct + cv + cg, were recorded (25,26). The patients in the CRAD group were further allocated to subgroup I (mild CRAD, score: 1–3) and subgroup II (moderate-to-severe CRAD, score: >3) based on the CBCS (22).

Clinical and laboratory indicators

Data on sex, age, body mass index (BMI), blood pressure hemoglobin (Hb), white blood cell (WBC) count, neutrophilic granulocyte percentage (N%), blood platelet (PLT), SCr, and Cys-C for three days before and after each patient’s ultrasound examination were collected from the hospital’s electronic medical record system. To measure Hb, the WBC count, N, and PLT, 2 mL of ethylenediaminetetraacetic acid potassium salt anticoagulated venous blood was collected the patients in the early morning fasting state. To measure SCr and Cys-C, 5 mL of venous blood was collected from the patients in the early morning fasting state and centrifuged for 10 min at 4,000 r/min.

Statistical analysis

The statistical analyses were performed using IBM SPSS Statistics 24.0 software and Origin2025. The Kolmogorov-Smirnov test was used to assess the normality of the quantitative data. The chi-squared test was used to compare the baseline characteristics of the patients, including sex. The non-normally distributed variables are expressed as the median (lower quartile, upper quartile), and were analyzed using the Mann-Whitney U test. The normally distributed variables are expressed as the mean ± standard deviation (SD), and were analyzed using the independent samples t-test. The relationships between the laboratory tests, pathological changes, and ultrasound parameters were analyzed using Spearman rank correlation coefficients; a correlation coefficient >0.75 was considered strong; a correlation coefficient between 0.4 and 0.75 was considered moderate; and a correlation coefficient <0.4 was considered poor. Binary logistic regression was used to select independent factors for the construction of the prediction models. Receiver operating characteristic (ROC) curves were used to calculate the area under the curve (AUC) values of the models; an AUC <0.65 indicated normal diagnostic efficacy, an AUC between 0.65 and 0.75 indicated good diagnostic efficacy, and an AUC >0.75 indicated excellent diagnostic efficacy. The optimal cut-off value was calculated according to the Youden index, and the sensitivity and specificity corresponding to the optimal cut-off value were calculated. The sample size was calculated according to the statistical method used for the main research purpose of this study, which was 10 times the number of indicators included; this study met the minimum sample size requirement. A two-sided P value <0.05 was considered statistically significant.

Results

A total of 188 transplanted kidney recipients were included in this study. The CRAD group comprised 92 patients, aged 18–68 years, of whom 75 were male and 17 were female, with a mean SCr value of 185.00 (131.00, 246.00) µmol/L at the time of biopsy; group 1 comprised 45 patients, and group II comprised 47 patients. The control group comprised 96 patients, aged 19–63 years, of whom 75 were male and 21 were female, with a mean SCr value of 108.50 (88.00, 131.80) µmol/L at the time of ultrasound examination. Table 1 sets out the other baseline characteristics of the patients, and Table 2 sets out the baseline characteristics of the patients in the CRAD subgroups.

Correlations between clinical data and ultrasound parameters

The EDV of the renal artery (r_s=–0.48, P<0.05; r_s=–0.39, P<0.05), segmental artery (r_s=–0.44, P<0.05; r_s=–0.37, P<0.05), interlobar artery (r_s=–0.40, P<0.05; r_s=–0.31, P<0.05), and arcuate artery (r_s=–0.39, P<0.05; r_s=–0.33, P<0.05) of the transplanted kidneys were significantly correlated with Cys-C and SCr. With the exception of the arcuate artery, moderate negative correlations were observed between the EDV of all the arteries and Cys-C. Poor negative correlations were observed between SCr and the EDV in all branches of the arteries. The RI of the renal artery (r_s=0.46, P<0.05; r_s=0.36, P<0.05), segmental artery (r_s=0.46, P<0.05; r_s=0.42, P<0.05), interlobar artery (r_s=0.48, P<0.05;=0.37, P<0.05), and arcuate artery (r_s=0.38, P<0.05; r_s=0.30, P<0.05) of the transplanted kidneys were also significantly correlated with Cys-C and SCr. With the exception of the arcuate artery, moderate positive correlations were observed between the RI of all the arteries and Cys-C. A moderate positive correlation was observed between the RI of the segmental artery and SCr (Figure 3A). Poor correlations were observed between BMI, Hb, N, eGFR, Cys-C, kidney length, the PSV of the renal artery, the EDV of the segmental artery, and the chronic pathological change score (Figure 3B).

Figure 3 Correlation analysis of parameters. (A) Correlation analysis between the ultrasound parameters and clinical indicators in the patients with CRAD. (B) Correlation analysis between the clinical indicators, ultrasound parameters, and pathology scores in patients with CRAD. The correlation coefficients between the indicators are shown in the upper right corner of the image. The circular pattern in the lower left corner represents significance, with the * sign representing a P<0.05. The larger the diameter of the circle, the smaller the P value and the more significant the correlation. Red represents a positive correlation and blue represents a negative correlation; the darker the color, the stronger the correlation. BMI, body mass index; CBCS, combined Banff chronicity score; CRAD, chronic renal allograft dysfunction; Cys-C, cystatin-C; EDV, end-diastolic velocity; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; N, neutrophilic granulocyte; PSV, peak systolic velocity; RI, resistance index.

Independent predictors of CRAD

The binary logistic regression analysis of the CRAD and control groups revealed significant predictive factors, including Cys-C, the EDV of the segmental artery, and the RI of the renal artery. While kidney length and the EDV of the segmental artery were identified as significant predictive factors in CRAD groups I and II (Table 3). The diagnostic performance of these independent factors were further evaluated. With a threshold of 0.72, the AUC of the RI of the renal artery was 0.834 [95% confidence interval (CI): 0.774–0.895] in the diagnosis of CRAD, and the sensitivity and specificity were 63.0% and 97.9%, respectively. Meanwhile, with a threshold of 19.80 cm/s, the AUC of the EDV of the segmental artery was 0.805 (95% CI: 0.742–0.869), and the sensitivity and specificity were 79.3% and 74.0%, respectively. The AUC value of the combined diagnostic model that included Cys-C, the RI of renal artery, and the EDV of the segmental artery reached 0.921 (95% CI: 0.882–0.960), with a sensitivity of 87.0% and a specificity of 83.3%. The EDV of the segmental artery was used to evaluate the degree of pathological changes in CRAD, differentiating between mild (CBCS ≤3) and moderate-to-severe CRAD (CBCS >3), and had an AUC of 0.627 (95% CI: 0.512–0.741) and a cut-off value of 17.24 cm/s. When it was combined with the kidney length, the AUC increased to 0.726 (95% CI: 0.622–0.830). The results are shown in Table 4 and Figures 4,5.

Figure 4 Parameters predicting the occurrence of CRAD in renal allograft. CRAD, chronic renal allograft dysfunction; Cys-C, cystatin-C; EDV, end-diastolic velocity; RI, resistance index.

Figure 5 Parameters for evaluating the degree of severity of pathologic changes in CRAD. CRAD, chronic renal allograft dysfunction; EDV, end-diastolic velocity.

Discussion

CRAD is an important cause of late graft failure following kidney transplantation, with 24.7% of recipients developing moderate-to-severe chronic allograft nephropathy at 1 year after transplantation and 89.8% of recipients affected at 10 years after transplantation (27). Currently, renal allograft biopsy is considered the “gold standard” for the diagnosis of chronic allograft dysfunction; however, it is an invasive procedure that can cause severe complications like gross hematuria, perirenal hematoma, and arteriovenous fistulas (28). Thus, accurate tools for the non-invasive evaluation of chronic changes need to be developed.

Doppler ultrasound is routinely used for the postoperative evaluation of renal transplant patients (24). Results on the relationship between histopathological findings and Doppler ultrasound parameters in renal disease are varied and often conflicting (29-32). Thus, the value of Doppler ultrasound parameters in the diseases of kidney transplantation is still unclear. In this study, we retrospectively collected Doppler ultrasound parameters and pathologic data from patients with CRAD during the same period to identify effective parameters.

Doppler ultrasound can be used to observe blood flow in all levels of vascular branches of the transplanted kidney, including the renal, segmental, interlobular, and arcuate arteries. According to the structural anatomy, the renal artery divides into segmental arteries at the renal papillary recess. The segmental arteries then continue toward the lateral aspect of the l renal pyramidal where they further divide into interlobar arteries, which advance to the corticomedullary junction and divide into arcuate arteries (33,34). When chronic changes occur in the transplanted kidney tissue, transplanted kidney perfusion decreases (35), the PSV and EDV are reduced, and the RI consequently increases. Similarly, this study found that the PSV and EDV of each arterial branch of the CRAD group were lower than those of the control group, while the RI of the CRAD group was higher than that of the control group.

Cys-C and SCr are reliable indicators of transplanted kidney function. Cys-C is not affected by gender, age, and diet, while SCr reflects severe impairment of transplanted kidney function. In the correlation analysis, the EDV and RI of the arteries were significantly correlated with the value of Cys-C and SCr, but the correlations between the ultrasound parameters and histologic features were poor. Cys-C and SCr values increase as the EDV value decreases, which suggests that Doppler ultrasound parameters could be used to predict changes in transplanted kidney function (36-38).

Consistent with our findings, some previous studies have suggested that the RI, while useful for identifying the presence of disease, may not be specifically correlated with distinct histologic features. In our study, while the RI of the renal artery could be used to differentiate between the overall CRAD and control groups, it could not be used to differentiate between the histologic subtypes of CRAD. Thus, the RI appears to be more reflective of the overall presence of chronic fibrotic and vascular injury rather than the specific underlying etiology, a notion supported by previous literature that links the RI more to general hemodynamic factors (39). The correlation between the Doppler ultrasound parameters and eGFR was poor in our study but several studies have reported conflicting results (36,37). Notably, the eGFR is calculated based on age, weight, sex, and SCr. However, eGFR values may be overestimated in individuals with obesity and underestimated in lean individuals (40), decreasing the reliability of the eGFR results of such patients.

In this study, Cys-C, the EDV of the segmental artery, and the RI of the renal artery were identified as important indicators of CRAD. Elevated Cys-C and a higher RI of the renal artery were associated with a higher risk of CRAD in the kidney transplant recipients, while a higher EDV of the segmental artery appeared to be protective. The AUC value for the RI of the renal artery was 0.834, and that for the EDV of the segmental artery was 0.805. Diagnostic performance improved when these parameters were combined in a model with Cys-C, yielding an AUC value of 0.921. Further, the model that combined the EDV of the segmental artery and kidney length achieved a higher AUC value for differentiating between mild and moderate-to-severe chronic lesions than either parameter alone. This finding can be explained by the underlying pathophysiology.

Characteristic pathological changes in CRAD, including TA, IF, and arterial intimal thickening, lead to a loss of vascular compliance. The resulting reduction in elasticity directly impairs diastolic flow, reflected as decreased EDV (28,41), Concurrently, these changes increase vascular resistance, leading to an elevated RI (42,43). Further, the progression of IF typically follows a gradient from the cortex toward the medulla (44,45). A reduction in overall kidney length likely reflects the advanced, global nature of this fibrotic process. Notably, the combined model of the EDV of the segmental artery and kidney length integrates the hemodynamic consequence of microvascular damage with a structural indicator of global disease burden, providing a more comprehensive assessment of chronic injury severity.

Previous studies have suggested that ultrasound flow parameters of the renal and segmental arteries are more informative than those of the distal arteries (25,28,46), and a correlation between an elevated RI of the renal artery and chronic pathological changes in the transplanted kidneys has been reported (30,32,47), which is consistent with our results. However, some studies have indicated that parameters measured in the interlobar or arcuate arteries may better reflect hemodynamic alterations in transplant kidney disease (48,49). This discrepancy may be attributed to the anatomical location and vascular course of these distal arteries, which can pose technical challenges for accurate measurement, leading to inconsistent findings across studies. Kidney size parameters are influenced by factors such as age and sex, with a more pronounced decrease in kidney volume observed in males aged over 70 years (50,51). Decreases in kidney volume and length have been shown to predict the development of CKD (50,52). The principal pathological features of CRAD (i.e., TA and IF) are major contributors to kidney volume reduction. Nevertheless, the clinical utility of the EDV of the segmental artery and kidney length in assessing the degree of pathological changes in CRAD requires further validation in larger studies.

This retrospective study had a number of limitations. First, patients were included in the study if they had undergone transplanted kidney biopsies at our hospital between 2011 and 2021; however, the biopsies from 2013 and before were described diagnostically using the 2009 version of the Banff classification, while those after 2013 were described using the 2013 and 2015 versions of the Banff classification; however, the 2009 version does not include C4d-negative antibody-mediated rejection, which might have contributed to the low number of CAMR patients in the CRAD group of this study sample (22,53). Second, due to the retrospective nature of the study, not all the clinical indicators that might influence the results could be included in the study, and a comparative analysis of other basic clinical data could not be conducted. Third, due to sample size constraints, we were unable to perform a more detailed etiological classification of the CRAD patients, or investigate the ability of Doppler ultrasound to differentiate among various causes of CRAD. Finally, due to the retrospective nature of this study, within-group concordance tests of Doppler ultrasound measurements were not performed. However, Doppler ultrasound is a well-established technology, the examiners were ultrasonographers with more than five years of experience, the procedure was standardized, and the quality of the images was checked, so the results of the study should be reproducible. However, within-group concordance tests for Doppler measurements should be considered in future prospective studies.

Conclusions

This study retrospectively analyzed the correlation between the pathological findings of transplanted kidneys and Doppler ultrasound parameters, and found that the RI of the renal artery and the EDV of the segmental artery can be used to effectively assess the occurrence of CRAD after renal transplantation. Further, a model that combined these parameters with Cys-C showed a high diagnostic capability for CRAD. Additionally, the EDV of the segmental artery and kidney length could be used to predict the severity of CRAD, but their value still requires further study with an expanded sample size. Clinical and ultrasound indicators are complementary, and a combined diagnostic model could significantly assist in clinical decision-making.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1573/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1573/dss

Funding: This work was supported by the National Natural Science Foundation of China (No. 82102067), the Key Research and Development Program sponsored by Chengdu Science and Technology Bureau (No. 2022-YF05-01498-SN), and 1·3·5 Project for Disciplines of Excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University (No. 2020HXFH049).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1573/coif). All authors report that this work was supported by the National Natural Science Foundation of China (No. 82102067), the Key Research and Development Program sponsored by Chengdu Science and Technology Bureau (No. 2022-YF05-01498-SN), and 1·3·5 Project for Disciplines of Excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University (No. 2020HXFH049). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee on Biomedical Research, West China Hospital, Sichuan University (No. 2022453) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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