Usefulness of Doppler ultrasound for the early diagnosis of diabetic nephropathy in type 1 diabetes mellitus

Abstract

Purpose

Early diagnosis and management of diabetic nephropathy (DN) might prevent or delay its progression to end-stage renal disease. The purpose of this study was to investigate whether changes in the duplex Doppler resistivity index (RI) are useful for the early identification of renal involvement in children and adolescents with insulin-dependent diabetes mellitus and associated conditions.

Materials and methods

A total of 49 diabetic patients (two groups: 21 with DN and 28 without DN) were included in this study. DN was defined as 30–300 mg/l of albumin excretion in a random urine sample. The RI of the main renal arteries and their intrarenal branches (arcuate, interlobar) were evaluated with duplex Doppler ultrasound and correlated with age, renal length, duration of diabetes, and laboratory examinations.

Results

The mean age did not significantly differ between the two groups. The patients with DN had a significantly longer duration of type 1 diabetes (p = 0.02). The majority of patients (90.5%) had mild renal involvement with microalbuminuria and normal renal function. The mean RI was normal in both groups of patients, with no significant difference between the two groups.

Conclusion

The RI did not increase in the early clinical stage of DN and was not a reliable marker for the screening of DN in patients with type 1 diabetes mellitus.

Introduction

The incidence of childhood-onset insulin-dependent diabetes mellitus has significantly increased worldwide, particularly in children younger than 5 years old [1]. Diabetic nephropathy (DN) is a serious complication of type 1 diabetes mellitus, occurring in about one-third of the patients [2].

Clinically evident diabetic microvascular involvement is extremely rare in childhood [2, 3], and overt nephropathy has been reported in less than 1% of patients [1]. However, structural and functional changes might develop before clinically evident DN [1, 2]. Therefore, early identification of renal involvement might prevent or delay the progression of DN to end-stage renal disease [3].

Microalbuminuria is the current diagnostic biomarker of DN, with low sensitivity and specificity [3, 4]. Therefore, the identification of noninvasive and reliable diagnostic approaches is crucial for the optimal management of these patients.

Renal vascular involvement has been considered the main pathogenic mechanism of DN [2]. Microangiopathy with renal artery stenosis might be related to early renal enlargement, hemodynamic factors, and tubulointerstitial damage in the pre-albuminuric reversible stage or late glomerular atherosclerosis with increasing resistivity against the blood flow in afferent vessels [5–7].

The resistivity index (RI) is a noninvasive and reliable index of intrarenal blood flow in patients with DN [2]. An elevated intrarenal RI has been considered an important predictive marker of incipient renal impairment in both diabetic and non-diabetic kidney disorders [5, 6]. Therefore, early diagnosis of DN might be made by measuring the renal vascular RI with duplex Doppler ultrasound [4].

However, findings regarding the correlation between the intrarenal RI and the clinical stage of DN remain debatable in both children and adolescents [1, 2, 4]. This study was performed to investigate the usefulness of conventional and duplex Doppler ultrasound of renal vasculature for the early diagnosis of DN and to examine the correlation between intrarenal RI with urine protein excretion and renal function in these age groups with type I diabetes mellitus.

Materials and methods

This is a cross-sectional study on 49 patients with type 1 diabetes mellitus (22 males, 27 females), who attended our diabetic clinic in 2018–2019. Of these patients, 21 (42.85%) had renal involvement. The study was approved by the local Ethics Committee (ethical code: IR: GOUMS. REC.1396.19), and informed consent was obtained from both groups with and without DN. Diabetes was defined as a fasting blood sugar level ≥ 125 mg/dl or a blood sugar level ≥ 200 mg/dl. Patients at late childhood and adolescence (10–19 years old) with a history of at least 3 years of diabetes were included in the study. However, the data of 5 children aged 6–8 years with a history of at least 3 years of diabetes were also evaluated.

Excluded from the study were patients with recently diagnosed diabetes mellitus, urinary tract obstruction, a glomerular filtration rate (GFR) < 60 ml/min/1.73 m², non-diabetic renal glomerular or tubulointerstitial disease, abnormal urinary sediment, cardiac or cerebral disorders, peripheral vascular disease, hypertension, metabolic disorders, nephrolithiasis, diabetic ketoacidosis, peripheral vascular disease, obesity (body mass index > 40 kg/m²), drugs (vasodilators, angiotensin-converting-enzyme inhibitors), a single kidney, chronic inflammation, and urinary tract infection.

The GFR was calculated using the Schwartz formula, K.L/Cr, where K is a constant coefficient, depending on muscle mass and age (K is 0.55 for children, 0.552 for girls, and 0.7 for boys); L is the renal length, measured by standard methods and expressed in cm; and Cr is the amount of serum creatinine, measured with the Jaffe enzymatic method and expressed in mg/dl. Blood pressure was recorded at least 3 times in the resting position.

Urine albumin was measured in fresh morning samples with an enzyme-linked immunosorbent assay (ELISA) kit provided by Orgentec Diagnostika GmbH (Mainz, Germany) and was expressed as normal (< 30 mg/l), microalbuminuria (30–300 mg/l), and macroalbuminuria (> 300 mg/l) in 2 out of 3 measurements over a 2- to 3-month period.

The fasting blood glucose level was measured by the glucose oxidase method. HbA1c concentration was measured every 3 months and was considered good control (6–7.9%), fair control (8–9.9%), and poor control (≥ 10%).

The flow velocity of renal vasculature was evaluated by real-time pulsed color duplex Doppler sonography during fasting to avoid bowel gas impression. To reduce unwanted biases in performing Doppler sonography and measuring the flow indices, all color Doppler studies were done by a single expert pediatric radiologist and with the same brand of sonographic device. In addition, to reduce interstudy differences, the measurements were optimized and standardized using automated I-Scan software of the Philips sonographic devices. The main renal artery and intrarenal branches (segmental and interlobar) of the upper, middle, and lower thirds of each kidney were evaluated in supine, lateral, and prone positions. The average value of three measurements were taken for analysis. The RI was measured according to the following formula: RI = PSV – EDV/PSV, in which PSV means peak systolic velocity, and EDV means end diastolic velocity. Normal values of the renal RI are in the range of 0.47–0.70, with a < 5–8% difference between the two kidneys [5].

Statistical analysis

All values were expressed as the mean ± SD. Statistical analysis was performed with SPSS version 21.0 software. Student’s t test and one-way ANOVA were used for the comparison of normally distributed variables, and the Mann–Whitney U test for the comparison of non-normally distributed variables. Categorial variables were compared with a Chi-square test. The correlation between variables was evaluated using Pearson’s correlation coefficient and Spearman’s test. A p value < 0.05 was considered statistically significant.

Results

A total of 49 patients with diabetes (two groups: 21 with DN and 28 without DN) were included in this study. The patients’ mean age did not significantly differ between the two groups. The patients with DN had a significantly longer duration of diabetes (p = 0.02), with a higher serum glucose level (p = 0.05) and higher urine albumin excretion (p < 0.001). The mean renal length and the GFR were normal in both groups of patients with no significant difference between the two groups (Table 1). The majority of patients (90.5%) had microalbuminuria (G1A2), and 2 patients had macroalbuminuria (G1A3). In the patients with DN, the mean RI of the left kidney had a significant negative correlation with the length of the right (p = 0.03, r = − 0.473) and left kidneys (p = 0.017, r = − 0.514).

Table 1.

Comparison of variables in patients with and without diabetic nephropathy

Variables	With nephropathy	Without nephropathy	Pv
Age (y)*	14.24 ± 3.64	13.86 ± 2.88	0.68
Gender (M/F)*	13/8	9/19	0.038
BMI* (kg/m2)	18.90 ± 3.57	20.25 ± 5.70	0.43
Right kidney length (mm)	96.57 ± 7.91	99.93 ± 10.74	0.23
Left kidney length (mm)	98.14 ± 9.13	102.86 ± 10.81	0.11
Right RI* (cm/s)	0.61 ± 0.04	0.59 ± 0.04	0.095
Left RI (cm/s)	0.62 ± 0.04	0.55 ± 0.24	0.06
Duration of diabetes (y)	7.24 ± 3.50	5.32 ± 2.34	0.02
FBS* (mg/dl)	199.19 ± 105.84	150.53 ± 64.40	0.05
Cr*(mg/dl)	0.71 ± 0.24	0.65 ± 0.19	0.30
BUN* (mg/dl)	21.09 ± 10.75	21.04 ± 6.18	0.52
HbA1C (%)	9.69 ± 2.10	9.978 ± 2.10	0.41
GFR* (cc/min/1.73m2)	132.02 ± 32.67	142.14 ± 47.27	0.40
Urine albumin (mg/l)	160.62 ± 127.30	14.86 ± 10.43	< 0.001

y year, M male, F female, BMI body mass index, RI resistivity index, FBS fasting blood sugar, Cr creatinine, BUN blood urea nitrogen, GFR glomerular filtration rate

Discussion

Conventional and Doppler ultrasound have been extensively used for diagnostic, therapeutic, and prognostic assessments of different renal disorders, including DN [5, 8].

The monitoring of renal dimensions may identify early stages of diabetic renal involvement [9]. Previous studies showed renal enlargement and parenchymal thickening in the early pre-albuminuric stages of DN, which decreased in the advanced phase, with renal scarring and renal dysfunction [10–12]. In our study, the mean renal length and GFR were normal in both groups of patients with and without DN, with no significant difference between the two groups, indicating the early clinical stage of DN, with no renal enlargement or hyperfiltration.

The Doppler RI has been suggested to be a reliable, noninvasive, and easily applicable method for investigating intrarenal vascular resistance [1] and indirectly estimating the 24-h urine protein excretion in adult patients with DN [13].

Some of the previous studies showed renal artery stenosis with an increased RI in patients with DN, with or without renal dysfunction, and prior to microalbuminuria [2, 3, 12, 14, 15], and suggested Doppler ultrasound as an early, sensitive, and noninvasive test for predicting the preclinical stage of incipient DN [1–3, 14].

A positive correlation has been reported between the renal RI and the HbA1C level, duration of disease, estimated GFR, and urine albumin excretion [1, 2, 8, 16].

Meanwhile, proteinuria, a high serum creatinine level, and an RI ≥ 70 were independent predictors of progressive renal disease in a study by Milovanceva et al. [17]. However, Ghaffar et al. found no correlation between the RI and these variables [4].

In our patients, the mean RI of both kidneys were in the normal range, with no significant difference between the two groups, which could be related to mild early renal involvement, without advanced nephropathy and renal atherosclerosis.

Similarly, Otken et al. showed no significant difference between the mean RI in diabetic patients with or without microalbuminuria, with no correlation with hyperfiltration. They concluded that Doppler ultrasound was not useful for the early detection of renal involvement in these patients [18].

Meanwhile, Platt et al. found normal renal RI values in patients without renal involvement or in the early clinical stages of DN, which increased in established and advanced nephropathy, with a positive correlation with decreased renal function, proteinuria, and poor renal outcome [19].

In a study by Brkljacić et al., the RI increased in patients with progressive DN, which was correlated with age, serum creatinine, and systolic or diastolic blood pressure [20]. In their study, the RI was not superior to other parameters for predicting progressive DN.

We conclude that in our study, the RI did not increase in the early clinical stage of DN, with mild renal involvement. The RI was not a reliable indicator for the early diagnosis of DN, compared with urine albumin excretion, and measuring urine albumin is recommended for the early screening of DN in children with type 1 diabetes mellitus.

Further multicenter studies are needed in larger groups of patients with mild and severe DN to identify the exact changes in RI and to determine the usefulness of the RI as a marker of renal involvement in patients with type 1 diabetes mellitus.

Compliance with ethical standards

Conflict of interest

The authors declared no conflict of interest.

Ethical approval

The study was in accordance with the ethical standards of the institutional research committee.

Informed consent

Informed consent was obtained from all participants in this study.