|Year : 2022 | Volume
| Issue : 1 | Page : 27-32
Utility of renal resistive index in children with nephrotic syndrome
Swarnim Swarnim1, Mohsina Naj1, Mukta Mantan1, Anju Garg2
1 Department of Pediatrics, Maulana Azad Medical College and Associated Lok Nayak Hospital, University of Delhi, New Delhi, India
2 Department of Radiology, Maulana Azad Medical College and Associated Lok Nayak Hospital, University of Delhi, New Delhi, India
|Date of Submission||29-Nov-2021|
|Date of Decision||10-Jan-2022|
|Date of Acceptance||16-Feb-2022|
|Date of Web Publication||28-Jun-2022|
Department of Pediatrics, Maulana Azad Medical College, University of Delhi, New Delhi - 110 002
Source of Support: None, Conflict of Interest: None
Background: Renal resistive index (RRI) is one of the Doppler parameters that provide information about arterial impedance. While its utility has been explored in chronic kidney disease and obstructive uropathy, its role in glomerular diseases remains less defined. Aim: This study aimed to measure RRI in children (6–18 years) with nephrotic syndrome, both steroid sensitive (SSNS) and steroid resistant (SRNS), currently in remission. Setting and Design: This cross-sectional study was done over 1 year at a tertiary care teaching hospital from March 2017 to March 2018. Methods: Renal Doppler ultrasound was done and RRI was measured at the main renal, arcuate, and interlobar arteries for both the kidneys during disease remission. Detailed information of disease type, biopsy, and therapy was recorded. Baseline biochemical investigations were done to confirm disease remission. Results: Fifty patients (25 each with SSNS and SRNS) were enrolled; the mean age was 12.6 years. The mean RRI at the interlobar and arcuate arteries was elevated in SRNS in all three poles of both the kidneys as compared to the SSNS with a significant difference at midpole (P = 0.04). RRI values were higher in children having focal segmental glomerulosclerosis (FSGS) compared to those with minimal change disease. The percentage of patients having an RRI value >0.6 was significantly higher in those who had received cyclosporine for >2 years as compared to those who received it for <2 years. Conclusions: Doppler RRI values were elevated for patients with SRNS compared to SSNS; changes were significant at the midpole of both kidneys. Children with FSGS and those on calcineurin inhibitors for more than 2 years are more likely to have higher RRI values.
Keywords: Cyclosporine, nephrotic syndrome, renal resistive index
|How to cite this article:|
Swarnim S, Naj M, Mantan M, Garg A. Utility of renal resistive index in children with nephrotic syndrome. Asian J Pediatr Nephrol 2022;5:27-32
| Introduction|| |
Nephrotic syndrome is a chronic disorder in children, with almost 90% of the patients having steroid-sensitive disease (SSNS). About 60% of the patients have a frequently relapsing or steroid-dependent course that requires prolonged use of steroids and other immunosuppressants such as alkylating agents, levamisole, and mycophenolate mofetil (MMF), while those with a steroid-resistant course (SRNS) are treated with drugs such as cyclosporine and tacrolimus. The prolonged use of calcineurin inhibitors (CNI) for 2–3 years can cause chronic tubulointerstitial damage in 25% of patients, histopathologically characterized by global glomerulosclerosis, tubular atrophy, striped interstitial fibrosis, and arteriosclerosis. A lower risk of nephrotoxicity has been reported with the use of tacrolimus.,, Most chronic changes of CNI use are often identified on renal biopsy alone making it necessary to perform kidney biopsy. This emphasizes the need for a noninvasive tool that can identify renal damage early.
Renal resistive index (RRI) is a measure of arterial impedance; it is calculated on Doppler ultrasonography and is defined as peak systolic velocity–end-diastolic velocity/peak systolic velocity. A value of 0.70 is considered to be the upper threshold of the normal RI in adults. In children, it is common for the mean RRI to exceed 0.70 through the ﬁrst 4 years of life, and subsequently decrease to below 0.6., The mean RRI values in children are age dependent and decrease with increasing age. The utility of RRI has been explored in chronic kidney disease (CKD) and obstructive uropathy as a monitoring and prognostic tool for disease progression.,, However, there are only a few studies on its utility in glomerular diseases with tubulointerstitial damage., This study was aimed to determine RRI in children (6-18 years) with SSNS and SRNS and to understand the correlation of RRI with disease duration, disease type, and duration of CNI therapy. As the RRI is less variable beyond 6 years of age, this age group was chosen.
| Methods|| |
This cross-sectional study was conducted in the Departments of Pediatrics and Radiology of a tertiary care teaching hospital from January 2017 to January 2018. The study was approved by the Institutional Ethics Committee and written informed consent/assent was obtained from the caregivers/patients prior to enrolment.
Children and adolescents between the ages of 6 to 18 years, diagnosed with SSNS or SRNS, and who were in complete or partial remission and attended the outpatient clinic were enrolled. Patients with SRNS had received at least 1-year of therapy with CNI. Patients were enrolled when they were normotensive and those with CKD stage 3 or more were excluded. As this was an exploratory study, a sample size of 25 each of SSNS and SRNS was taken. Baseline information of all patients including the age, diagnosis, duration of nephrotic syndrome, and disease type and details of immunosuppressants, anthropometry, and examination findings were recorded. To identify complete or partial remission and to monitor the kidney function, urine protein examination was done using dipsticks; 2 ml blood sample was drawn from each patient for biochemical investigations. Complete remission was defined as the presence of trace or negative proteinuria on dipstick examination and partial remission as 1 + or 2 + proteinuria for 3 consecutive days and serum albumin >3.0 g/dL, and no edema. Blood albumin levels of more than 3.0 g/dL and cholesterol levels below 200 mg/dL confirmed biochemical remission.
All patients with SSNS received either daily steroids or alternate-day steroids for the treatment of relapses; medications such as low-dose alternate-day steroids, cyclophosphamide, levamisole, and MMF were used for patients with frequent relapses or steroid dependence. For difficult-to-treat SSNS, CNI were used sparingly. Patients with SRNS underwent renal biopsy and were treated based on the biopsy findings. Children with minimal change disease, focal segmental glomerulosclerosis (FSGS), and mesangioproliferative glomerulonephritis were treated with CNI (cyclosporine or tacrolimus) along with alternate-day prednisolone in tapering doses. Cyclosporine was given at a dose of 4–5 mg/kg/d, while tacrolimus was given at doses ranging from 0.08 to 0.15 mg/kg/d in two divided doses. Most patients received therapy with an ACE inhibitor (enalapril 0.2–0.5 mg/kg/d). Both CNI were given for a period of 2–3 years; rarely longer in some patients dependent on these drugs. CNI toxicity was monitored primarily by looking at the blood level of creatinine, blood pressure, and clinical features of hirsutism and gingival hyperplasia. Routine monitoring of CNI levels could not be done for most patients due to financial constraints and nonavailability of testing. Renal biopsy was done for all the patients who were on prolonged CNI, i.e., for more than 2-years.
The renal color Doppler assessment was done in supine and lateral positions using a Philips ultrasound machine (model no – MCMD02AA) with a probe of 2–5 MHz. frequency. All ultrasounds were done by a single trained radiologist to avoid interpersonal variations. The kidneys were first scanned for length, breadth, cortical thickness, and echogenicity, followed by identification of interlobar and arcuate arteries. The Doppler spectral patterns of velocity–time graph were obtained for 3 consecutive times and an average of these value was taken. The RRI was measured manually at the upper, middle, and lower poles of each kidney separately, as follows:
These values were derived by the ultrasound machine based on the computer algorithm. The RRI values were identified separately for the main renal, interlobar and arcuate arteries for each kidney and both the poles.
Data were entered into a Microsoft Excel spreadsheet and then analyzed by statistical software program SPSS (Statistical product and service solution version 24) provided by IBM and GraphPad Prism version 5. Data were summarized as mean and standard deviation (SD) for numerical variables and count and percentages for categorical variables. Two-sample t-tests for a difference in mean were used for independent samples or unpaired samples. One-way analysis of variance was used to compare means of three or more samples for numerical data (using the F distribution). Unpaired proportions were compared by Chi-square or Fisher's exact test, as appropriate. Correlation was calculated by Pearson correlation analysis.
| Results|| |
A total of 50 (86% boys) children with nephrotic syndrome (25 SSNS and SRNS) were enrolled. The baseline characteristics of the study population are provided in [Table 1]. The mean SD age of children with SSNS and SRNS was 12.4 (2.7) and 12.8 (2.7) years, respectively. The mean age of onset of the disease was 5.7 (2.9) years for SSNS group and 5.2 (2.7) years for SRNS. A comparison of biochemical parameters of SSNS and SRNS patients did not reveal any significant difference in either group and all children were in remission and were normotensive [Table 1]. Among the 25 SSNS patients, 9 (36%) had an infrequently relapsing course, 9 (36%) had frequent relapses, and 7 (28%) had steroid dependence.
The length, breadth, and cortical thickness of the right and left kidneys of patients in SRNS and SSNS groups are shown in [Table 2]. The RRI values at interlobar and arcuate arteries at different poles of both kidneys are provided in [Table 3]. The mean RRI at the interlobar artery was elevated in the SRNS group in all the three poles of both the right kidney and left kidneys, as compared to the SSNS group. The difference was statistically significant only at the midpole of the right kidney (P = 0.04). The mean RRI at the arcuate artery was elevated in the SRNS group in all three poles of both kidneys, as compared to the SSNS group. The mean RRI of the arcuate artery at the midpole and lower pole of the right kidney and all poles of the left kidney was significantly increased in patients with SRNS compared to SSNS [Table 3].
Of 29 patients with a renal biopsy, changes of minimal change disease were present in 19, FSGS in 9, and membranoproliferative glomerulonephritis in one. Patients with FSGS had higher mean RRI values, though not statistically significant (P = 0.7). A positive correlation was found between duration of cyclosporine use and RRI. Correlation coefficient for the right interlobar artery was 0.06, left interlobar artery was 0.029, right arcuate artery was 0.262, and left arcuate artery was 0.268. P values were, however, insignificant.
In 31 of the 50 (62%) patients, cyclosporine was used for treatment; 10 (20%) received it for <2 years and 21 (42%) for more than 2 years. The proportion of patients with an RRI value >0.6 was significantly higher in those who had received cyclosporine for more than 2 years as compared to those who received it for shorter duration [Table 4]. This difference was most seen at the midpole of both interlobar and arcuate arteries.
| Discussion|| |
RRI has been used extensively for the diagnosis of conditions like renal artery stenosis and for assessing the risk factors for worse outcomes in patients with antenatal hydronephrois and CKD.,, Doppler sonography has been used for assessing the progression of arteriolar sclerosis and renal parenchymal damage in adults. However, its utility in children with an underlying renal disease such as nephrotic syndrome has not been widely examined.
In the present study, the mean age of enrolment was 12.4 years for SSNS and 12.8 years for SRNS patients. In previously done similar studies, only steroid-sensitive patients were enrolled and the effect of CNIs on RRI was not explored.,
The male:female ratio of 6.1:1 observed in our study was higher than previously reported., As most children were beyond 10 years of age at inclusion, the condition could have remitted in girls earlier and would have persisted in boys even at older age.
The biopsy findings showed that 55% of SRNS children had minimal change and 35% had FSGS. In a study on 250 children with nephrotic syndrome requiring biopsy, the most common lesions in SRNS patients were minimal change in 43.7%, followed by FSGS in 32.9%. Another study on 147 pediatric patients with SRNS found FSGS (38.5%) as the chief histopathological lesion, and minimal change disease in 23.2%.
Radiological examination showed that the mean length of the right kidney in patients with SRNS was smaller than SSNS patients though not statistically significant (P = 0.25); the mean breadth of both kidneys was smaller in SRNS compared to SSNS (P = 0.05 right kidney; P = 0.44 left kidney). This size variability could be a chance factor or due to a more prolonged and severe disease in children with SRNS. Overall, 20% of the patients had hyperechoic kidneys. A retrospective study on radiological records of 43 patients found 62% children with SRNS and 18% with SSNS had increased echogenicity (P < 0.05), and concluded that the presence of increased cortical echogenicity might be a feature of SRNS. It would be prudent to repeat the ultrasound in these patients, to see if the echogenicity is transient or has long-term consequences or sign of progression to CKD.
The mean RRI values for patients with SRNS were higher than SSNS, at the level of both arcuate and interlobar arteries. While the difference was statistically significant in almost all the poles for the arcuate artery, it was significant only at the level of midpole for the right interlobar artery (P = 0.04). Thus, the measurements of RRI at the arcuate artery may be a better indicator of chronic changes than the interlobar artery. RRI values were subdivided into three categories of <0.6, 0.6–0.7, and values of more than 0.7. Values between 0.6 and 0.7 were considered as borderline increased, whereas value >0.7 was considered high.
A previous study on 53 children with nephrotic syndrome showed similar values of RRI as their age-matched controls, and a statistically significant difference was seen only at the level of midpole of the left kidney. However, the distribution of SSNS or SRNS in their cohort was not specified and most patients were in relapse at the time of Doppler evaluation, which could have affected the results. In another study on children with SSNS, no significant difference between RRI in different categories of SSNS (first episode, frequent relapses, and infrequent relapses) was found and most patients were in relapse. The role of RRI has not been explored in children with SRNS disease where RRI values are expected to be higher as a result of prolonged CNI use and progression of the underlying disease. Furthermore, evaluation during relapses may elevate RRI transiently due to concomitant hypovolemia or acute kidney injury which occurs in a significant number of patients.
At the level of interlobar artery, almost similar number of patients in both minimal change disease and FSGS groups had RRI values above 0.6. At the level of arcuate artery, similar number of patients in both groups had RRI values above 0.6 for the right kidney, while the number was more (37.5% vs. 17.6%) for the FSGS group in the left kidney. No previous study has compared RRI values with biopsy findings in patients with nephrotic syndrome; hence, further confirmation of this observation is needed in future studies.
Cyclosporine was administered to a majority (62%) of patients enrolled in this study. An elevated (>0.6) RRI was seen at both interlobar and arcuate arteries for those who received the drug for more than 2-years compared to those who received it for a shorter duration. A positive correlation was also found between the duration of cyclosporine use and RRI. CNI tend to cause renal vasoconstriction primarily mediated by constrictors such as endothelin; prolonged use of these agents also causes tubulointerstitial damage. Both these vascular and tubulointerstitial changes tend to alter the RRI which has been shown to correlate with changes in renal vascular resistance. A study on 42 children with CKD showed that an increase in RRI fairly predicts the degree of glomerular sclerosis and interstitial fibrosis.
The primary limitations of our study were that it was a one-time observational study and the biopsy findings for calcineurin toxicity were not available for all patients; hence, sensitivity and specificity could not be calculated. Simultaneous RRI and biopsy findings might have given a better comparison. Furthermore, during Doppler study, the patients had to hold their breath for a few seconds, which was technically difficult in younger patients. This led to the enrolment of only older children.
| Conclusions|| |
We found that RRI was higher in patients with SRNS disease than SSNS, and in FSGS patients compared to minimal change. Prolonged use of cyclosporine also tends to increase the RRI values. Most changes in RRI were significant at the midpole of both kidneys and better appreciated at the level of arcuate arteries; these areas could be used primarily for screening purposes. However, further studies with larger number of patients and correlation of RRI to toxicity features on biopsy are needed to better define the role of renal Doppler in children with nephrotic syndrome.
Ethical clearance number Fno:-11/IEC/MAMC/2016/318.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]