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Renal Doppler Ultrasound Case Study

Original Research

Renal Duplex Sonographic Evaluation of Type 2 Diabetic Patients

Authors

  • Mancini Marcello MD,

    1. Istituto Di Ricovero e Cura a Carattere Scientifico, SDN Foundation, Institute of Diagnostic and Nuclear Development, Naples, Italy (M.Man., M.R.).
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  • Masulli Maria MD,

    1. Department of Clinical and Experimental Medicine (M.Mas., G.R., O.V.), Federico II University School of Medicine, Naples, Italy.
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  • Liuzzi Raffaele PhD,

    Corresponding author
    1. Institute of Biostructure and Bioimaging, National Research Council (M.Man., R.L., P.P.M.), Federico II University School of Medicine, Naples, Italy.
    • Address correspondence to Raffaele Liuzzi, PhD, Institute of Biostructure and Bioimaging, National Research Council, Federico II University School of Medicine, Via De Amicis 95, 80145 Naples, Italy.

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  • Mainenti Pier Paolo MD,

    1. Institute of Biostructure and Bioimaging, National Research Council (M.Man., R.L., P.P.M.), Federico II University School of Medicine, Naples, Italy.
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  • Ragucci Monica MSc,

    1. Istituto Di Ricovero e Cura a Carattere Scientifico, SDN Foundation, Institute of Diagnostic and Nuclear Development, Naples, Italy (M.Man., M.R.).
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  • Maurea Simone MD,

    1. Department of Biomorphological and Functional Science (S.M.), Federico II University School of Medicine, Naples, Italy.
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  • Riccardi Gabriele MD,

    1. Department of Clinical and Experimental Medicine (M.Mas., G.R., O.V.), Federico II University School of Medicine, Naples, Italy.
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  • Vaccaro Olga MD

    1. Department of Clinical and Experimental Medicine (M.Mas., G.R., O.V.), Federico II University School of Medicine, Naples, Italy.
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Abstract

Objectives

The purpose of this study was to evaluate the renal volume and intrarenal hemodynamics with duplex sonography in a group of diabetic patients with normal renal function in comparison to nondiabetic controls.

Methods

The renal volume and resistive index (RI) of segmental arteries were assessed by duplex sonography in 88 diabetic patients (44 male and 44 female; median age, 58 years [range, 37–69 years]) and 73 nondiabetic control participants (48 male and 25 female; median age, 53 years [range, 27–75 years]) without renal artery stenosis.

Results

Both renal volume and RI values in the diabetic patients were significantly higher compared to the controls (mean volume ± SD: diabetic patients, 197.3 ± 47.6 mL; controls, 162.5 ± 35.2 mL; P < .0001; RI: diabetic patients, 0.70 ± 0.05; controls, 0.59 ± 0.06; P < .0001). Renal hypertrophy was present even in diabetic patients without proteinuria (renal volume: patients without proteinuria, 198.3 ± 45.9 mL; controls, 162.5 ± 35.2 mL; P < .005). Patients with higher RI values had significantly greater proteinuria (RI <0.75, 15.9 mg/g [range, 4.2–1718.9 mg/g]; RI >0.75, 37.9 mg/g [range, 11.34–2087.0 mg/g]; P < .02).

Conclusions

Changes in renal volume and hemodynamics are detectable on sonography in diabetic patients. Those changes are also present in patients without proteinuria or signs of renal atherosclerosis and with both normal and increased glomerular filtration rates. These results indicate a potential role of duplex sonography in the early identification of morphologic and hemodynamic renal changes in type 2 diabetic patients.

Abbreviations
GFR

glomerular filtration rate

MR

magnetic resonance

RI

resistive index

A high proportion of patients with type 2 diabetes are found to have microalbuminuria and overt nephropathy shortly after the diagnosis of diabetes because diabetes is usually present for many years before the diagnosis and also because the presence of albuminuria might be less specific for the presence of diabetic nephropathy, as shown by biopsy studies.14 Without specific interventions, 20% to 40% of type 2 diabetic patients with microalbuminuria progress to overt nephropathy. Recent studies have shown that pharmacologic treatment instituted at a very early stage, ie, before the appearance of the proteinuria, can prevent the onset of nephropathy.5

Hypertension in type 2 diabetes can be related to underlying diabetic nephropathy, coexisting essential hypertension, or other secondary causes such as renal vascular disease. Both systolic and diastolic hypertension markedly accelerate the progression of diabetic nephropathy, but aggressive management can greatly decrease the speed at which the glomerular filtration rate (GFR) falls.2

Duplex sonography provides an easily applicable, non-invasive, and well-established method for investigating renal morphologic characteristics, diagnosing renal artery stenosis, and measuring vascular resistance in the renal parenchyma.69 The renal resistive index (RI), measured by duplex sonography, has been shown to be associated with features of diabetic nephropathy and its progression over time, independent of albuminuria,10 and in a multivariate regression analysis, the RI was an independent predictor of declining renal function.11 An increased RI was suggested to reflect the renal scarring process, resulting in a reduction of the intrarenal vessel area and a consequent increase in intrarenal vascular resistance.7

Moreover, serial measurement of the renal volume could be important for evaluating patients with renal disease because changes in renal size could indicate irreversible damage. Several experimental studies have reported that renal enlargement precedes renal hyperfunction in the early phase after the onset of experimental diabetes.1218 Although an increase in renal mass is well described in animals, the changes in renal volume after clinical onset of diabetes in humans and the relationship with the RI have not been extensively studied.

The aim of the study was to evaluate the renal volume and intrarenal hemodynamic abnormalities with grayscale and Doppler sonography in diabetic patients without renal artery stenosis in comparison to nondiabetic controls.

Materials and Methods

This study included 92 type 2 diabetic patients with more than 1 year of disease, mild coexistent hypertension, and body mass index of 40 kg/m2 or less, were consecutively recruited over 6 months at an outpatient diabetes clinic. Markedly obese patients, according to World Health Organization criteria (ie, >40 kg/m2),19 were not recruited because of the difficulty related to sonographic examinations. Forty-nine of the 92 patients had a normal GFR (creatinine clearance ≥90 mL/min/1.73 m2) and 43 had a mildly decreased GFR (60–90 mL/min/1.73 m2).20 The diagnosis of type 2 diabetes was established according to World Health Organization criteria.21 Moreover, 73 nondiabetic control participants with mild hypertension, consecutively recruited among hospital employees, were also studied. The protocol was approved by the Ethics Committee of the university department, and all patients and controls gave informed consent.

A full clinical evaluation was performed to obtain information about the smoking status, clinically overt cardiovascular disease, and current therapy. Spot urine was collected for measurement of the albumin to creatinine ratio and routine urinalysis. Fasting venous blood samples were taken for determination of serum electrolyte, creatinine, blood glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and hemoglobin A1c values by standard laboratory methods. Serum and urinary creatinine was measured with an automatic analyzer, and creatinine clearance was calculated by a formula from the urine creatinine concentration, urine flow rate, and plasma creatinine concentration.20 The blood pressure was measured according to the American Heart Association blood pressure measurement recommendations22 and classified as hypertensive according to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.23

The albuminuria status (albumin to creatinine ratio) was defined according to the standards of medical care of the American Diabetes Association24 as normal (<30 μg/mg), microalbuminuria (30–299 μg/mg) or macroalbuminuria (≥300 μg/mg). To exclude severe renal artery stenosis, all diabetic patients underwent magnetic resonance (MR) angiography. Magnetic resonance imaging was performed on a 1.5-T system (Gyroscan Intera; Philips Healthcare, Best, the Netherlands) using a phased array body coil. Dynamic gadopentetate dimeglumine–enhanced (Magnevist; Schering AG, Berlin, Germany) MR angiography was performed with a 3-dimensional gradient-recalled echo sequence. Images were interpreted by an attending radiologist trained in body MR imaging. The defining criterion for severe renal artery stenosis was a narrowing of 50% or greater.

Sonographic Study

All examinations were performed by 2 trained sonographers with more than 10 years of general and vascular sonography experience using an HDI 5000 Sono-CT color Doppler system (Philips Healthcare, Bothell, WA) equipped with a 5–2-MHz curved array transducer. The operators were unaware of the participants' clinical details and laboratory findings. All participants were scanned in the supine, lateral, and prone positions after an overnight fast to minimize the presence of bowel gas. A complete B-mode sonographic evaluation of the renal morphologic characteristics was performed. The renal volume in cubic centimeters was estimated in all participants according to the ellipsoid formula25,26 and expressed for each participant as the mean of the values obtained for both kidneys (mean renal volume). The renal area index was measured as the mean renal volume/body surface area.27,28 The presence of renal artery stenosis was evaluated with Doppler sonography using validated criteria.2931

The pulsed Doppler signal was collected in the segmental arteries in the longitudinal position for measuring the Doppler spectrum of both kidneys at the optimal angle (0°–10°; Figure 1A). Color Doppler imaging was used to identify the segmental arteries, defined as the arteries in the region from where the distal arteries penetrate the renal parenchyma to the sinoparenchymal junction. The pulsed Doppler exploration was performed without angle correction and with a sample volume of 5 mm. The paper speed was 100 mm/s. Waveforms were optimized for measurement using the lowest pulse repetition frequency without aliasing, the highest gain without obscuring flow by surrounding background noise, and the lowest wall filter. Six reproducible waveforms from arteries of the upper, middle, and lower thirds of each kidney were obtained. These waveforms were averaged to arrive at the RI, and the mean RI value for both kidneys was used for statistical analysis. The mean duration of each examination was 30 minutes.

Interobserver variability between the investigators performing the sonographic examinations was assessed in a group of 26 participants in whom the RI was measured within 1 hour by both investigators in a blinded fashion and was reported in a previous study (interobserver variability interval, −0.035 ± 0.044; reproducibility coefficient, 0.0043).32

Statistical Analysis

To verify whether the data were normally distributed, the D'Agostino-Pearson test was used. If the distribution was normal, parametric statistics were used, and data were expressed as mean ± standard deviation; to compare two samples, an unpaired Student t test was used, whereas comparisons among groups were performed by means of 1-way analysis of variance; post hoc analysis was performed with the Student-Newman-Keuls test. If the normality of the distribution was not assessed, nonparametric statistics were used, and data were expressed as median and range. To compare two samples, an unpaired Mann-Whitney U test was used. The correlation between two variables was assessed by the Spearman coefficient. Categorical data were expressed as percentages. The χ2 or Fisher exact test was applied when appropriate. Two-tailed P < .05 was considered significant. Statistical analyses were performed with MedCalc version 12 software (MedCalc Software, Mariakerke, Belgium).

Results

In 1 patient, a sonographic scan was considered technically inadequate because no accurate depiction of renal morphologic characteristics could be obtained, and the Doppler signal was not adequately detected. The MR examinations disclosed severe main renal artery stenosis and kinking in 2 patients and a renal mass in another patient. These 4 patients were excluded from statistical analysis to avoid the interference of these conditions on renal volumes and hemodynamics. Finally, the statistical analysis included 88 patients without renal artery stenosis. The median age of the patients was older than that of the controls but not statistically different.

The clinical and sonographic characteristics of the diabetic patients and nondiabetic controls are summarized in Table 1. Of the diabetic patients, 59 (67.0%) were normoproteinuric; 21 (23.9%) were microproteinuric; and 8 (9.1%) were macroproteinuric.

No patient had RI values that differed by greater than 5% between the two kidneys. The diabetic patients had mean renal volume, renal area index, and RI values that were significantly higher than those of the nondiabetic controls (Table 1). No correlations were found between age and the mean renal volume, renal area index, and RI in the diabetic patients and controls; therefore, it was concluded that the observed differences were not due to the age differences between the groups. The mean renal volume, renal area index, and RI values stratified for the presence of proteinuria in the diabetic group in comparison to the nondiabetic group are reported in Table 2 and Figures 2–4. The diabetic patients with higher RI values (>0.75) had a longer diabetes duration compared to the patients with lower RI values (≤0.75), had greater protein urine excretion (RI <0.75, 15.9 mg/g [range, 4.2–1718.9 mg/g]; RI >0.75, 37.9 mg/g [range, 11.34–2087.0 mg/g]; P < .02), and had lower creatinine clearance, although this last difference was not considered clinically significant.

Patients with different degrees of protein excretion had different RI values. The normoalbuminuric and microalbuminuric diabetic patients had significantly higher RI values than the controls and nonsignificantly lower RI values than the macroalbuminuric diabetic patients. The normoalbuminuric diabetic patients had a significant increase in renal volume (≈26%) compared to the controls and macroalbuminuric patients but not the microalbuminuric patients (Figures 2–4).

Male/female44/4448/25χ2NS
Age, y58 (37–69)53 (27–75)UNS
Duration of diabetes, y10 (1–44)   
Body mass index, kg/m228.9 (19.9–37.1)25.9 (18.5–40.1)t.004
Systolic blood pressure, mm Hg140 (98–182)120 (94–156)UNS
Diastolic blood pressure, mm Hg80 (60–100)75 (60–96)UNS
Smokers21/88 (24)17/73 (23)χ2NS
Glycemia, mmol/L164 (89–365)88 (71–109)U<.0001
Creatinine, mg/dL0.86 ± 0.200.89 ± 0.10t.028
Creatinie clearance, mL/min/1.73 m292 ± 1789 ± 22tNS
Mean renal volume, mL197 ± 47.6162.5 ± 35.2t<.0001
Renal area index, mL/m2107.1 (63.7–208.9)85.4 (52.0–121.9)U<.0001
Resistive index0.70 ± 0.050.59 ± 0.06t<.0001
n59/8821/888/8873
Mean renal volume, mL198.3 ± 45.9a198.0 ± 51.6187.9 ± 54.5162.5 ± 35.2
Renal area index, mL/m2109.5 ± 24.6a110.3 ± 28.8a105.4 ± 22.4a85.2 ± 14.5
Resistive index0.69 ± 0.04a,b0.69 ± 0.05a0.73 ± 0.04a0.59 ± 0.06

The RI values of the diabetic group showed a positive correlation with the degree of proteinuria (P = .001); ie, higher RI values corresponded to a higher degree of proteinuria (Figure 3). A positive correlation was found between the renal volume and renal function expressed as creatinine clearance (Spearman test, r = 0.312; P < .01) as well as between the RI and the disease duration (Spearman test, r = 0.398; P < .001). Moreover, no correlation was found between the RI and blood pressure, age, or body mass index.

Discussion

In this study, the renal volume of the diabetic patients was significantly higher than that of the nondiabetic controls. The kidney volume corrected for body surface area (renal area index) was increased by 26% in the diabetic patients. Stratifying for the degree of proteinuria, the greatest degree of nephromegaly was present in the normoalbuminuric patients with normal renal function (Figures 2 and 3). Diabetic kidney hypertrophy-hyperfunction syndrome is a well-established phenomenon that precedes changes in albuminuria by several years33 and predicts progression into microalbuminuria and overt renal disease.2,3,6,34 Renal enlargement occurs shortly after the induction of hyperglycemia, and it has been shown that the protein content rises in parallel to the kidney weight. Similarly, an increased protein to DNA ratio has been measured after a few days, indicating hypertrophy of the cells.14,35,36 In a longitudinal study of 146 normoalbuminuric patients, an increased kidney volume at baseline, but not hyperfiltration, was a predictor of progression to microalbuminuria in 27 patients.37

The increase in renal volume during the early phase of diabetic nephropathy observed in diabetic patients could be associated with a reduction in the surface ratio of capillaries to tubules and might cause reduced perfusion and interstitial fibrosis. Hyperfiltration and hypertrophy are the first abnormalities seen in the kidneys in both types of diabetes and can be ideal parameters for intervention because the GFR is well preserved. The structural and functional changes are all reversible and can be decreased by improving metabolic control, strict blood pressure control, and treatment with angiotensin-converting enzyme inhibition or angiotensin 2 receptor blockade. From a clinical viewpoint, hyperfiltration is not a parameter of practical value for daily management of patients because it is too problematic to measure, whereas kidney volume measurement could be a potential tool for early identification of diabetic nephropathy. In this study, nephromegaly was the only detectable alteration in the diabetic patients during the prealbuminuric phase, when renal abnormalities are not detectable by the noninvasive methods normally used and recommended by the scientific community for diabetic nephropathy screening.

In animal models, prevention of early hypertrophy-hyperfunction has already been shown to avoid the development of diabetic nephropathy.38,39 Future studies will need to address the independent role of nephromegaly not only in the evolution of albuminuria but also in the subsequent decline of the GFR and whether it is a marker of glycemic control or exerts a pathogenetic role in human diabetic nephropathy.

In this study, higher RI values were also observed on Doppler sonography in the diabetic patients (Figures 1B and 4). Major variations were detected at advanced stages of diabetic nephropathy but less so in the early course of nephropathy (Figure 4 and Table 2).

The RI used to grade intrarenal resistance with sonography represents the intrarenal resistance downstream of the measuring site. It is the easiest of all known resistance parameters to record,40 correlates with biopsy results,41,42 and might aid in the management of renal disease.4346 Radermacher et al8 reported an RI of 0.8 or higher to be the strongest predictor of allograft loss among 44 risk factors included in a multivariate analysis, and the RI was correlated with several histologic markers of intrarenal damage.

The RI increase in our group of diabetic patients did not depend on the chronologic age but on the duration of diabetes. This finding can be an indication of a disease-specific alteration. How much the 3 different renal vascular beds (preglomerular vessels, glomerular capillaries, and postglomerular vessels) contribute to the elevated RI is unclear. In diabetic patients, renal artery disease is more frequent in the intrarenal vessels than in the main renal artery, and it is possible that during the very early prealbuminuric phase, patients have more pronounced vasoconstriction, even without overt nephropathy.

A possible explanation for our study results may be the following: (1) at an early stage of the disease, renal damage is located primarily in the glomeruli, in which case, a normal RI would be expected47; and (2) at an advanced stage of the disease, the glomeruli become sclerotic, and tubules become atrophic with increasing interstitial fibrosis. All of these factors can lead to an increase in the RI.42 Moreover, advanced arteriosclerosis in intrarenal arteries at an advanced stage of diabetic nephropathy may contribute to the increase in the RI.48 Therefore, renal hypertrophy and the increase in the RI could represent two different phases: renal enlargement is a prealbuminuric reversible step of renal involvement in diabetes mellitus, whereas the RI increase indicates the progression of disease with renal scarring, which precedes the appearance of albuminuria.4952

There is evidence that suggests that the risk of developing diabetic nephropathy begins when urinary albumin excretion values are still in the normoalbuminuric range53,54; however, excluding biopsy, no humoral or imaging parameter exists that can reveal earlier stages of nephropathy. Diabetic nephropathy is a progressive condition that often heralds increasing creatinine as the final manifestation, and as it evolves, the risk of cardiovascular complications increases. At present, treatment during the later stages of the condition is unable to preserve renal function or alter the burden of cardiovascular events. Future research could evaluate whether the progression of nephropathy and cardiovascular morbidity and mortality could be prevented by early treatment in patients with an increased renal volume, a higher RI, or both. Sonography may identify patients with nephropathy at a very early stage and may contribute to early diagnosis and prevention of disease progression.

Ancillary

Article Information

DOI

10.7863/ultra.32.6.1033

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© 2016 by the American Institute of Ultrasound in Medicine

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Publication History

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Keywords

  • diabetes;
  • diabetic nephropathy;
  • proteinuria;
  • renal hypertrophy;
  • resistive index

References

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  • 2Bakris GL, Williams M, Dworkin L. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis2000; 36:646–661.
  • 3Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care2005; 28:164–176.
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Methods

Ultrasonographic measurements of the hemodynamic parameters over the fetal renal artery were made between 35 weeks' and 40 weeks' gestation in 66 patients with isolated oligohydramnios and 60 patients with normal amniotic fluid volumes. Apart from oligohydramnios in the study group, neither the patients in the study group nor the control group had any fetal or maternal anomalies or complications. The measured parameters of hemodynamic changes over the fetal renal artery included the resistance index/pulsatility index, systolic/diastolic ratio, acceleration time, and blood flow using spectral and power Doppler modalities. In addition, fetal renal volume, birth weight, and the Apgar score were measured and recorded in both groups prior to and after delivery of the infants. The receiver operating characteristics and the two-tailed t test were used for statistical analyses.

Results

Compared with the control group, the systolic/diastolic ratio and acceleration time were higher in the isolated oligohydramnios group, but with a lower fetal renal blood flow.

Conclusion

Our study shows that isolated oligohydramnios is related to fetal hemodynamic changes in the fetal renal artery and the regulatory mechanisms of the vascular bed.

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