New strategy of color and power doppler sonography combined with DMSA in the assessment of acute pyelonephritis in infants

doi:10.21203/rs.2.11744/v1

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New strategy of color and power doppler sonography combined with DMSA in the assessment of acute pyelonephritis in infants

https://doi.org/10.21203/rs.2.11744/v1

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Objectives

The purpose of this study was to evaluate the clinical value of color and power doppler sonography (CPDS) when combined it with 99mTc-dimercaptosuccinic acid scintigraphy (DMSA) in assessment of acute pyelonephritis (APN) in infants.

Methods

A total of 79 children with APN , including 52 males and 27 females, age range 1 month to 3 years old. All patients underwent laboratory inspection including urinary routine test, clean medium urine culture, urinary β2 microglobulin (β2-MG), urinary N-acetylglucosaminidase (NAG), blood routine test, C-reactive protein(CRP), renal function, serum electrolyte and urinary ultrasound. All 79 patients underwent CPDS and DMSA within 48 hours of fever.

Results

All 79 patients with fever. The peripheral blood routine showed elevated white blood cells in 75 cases, normal in 4 cases, CRP increased in 77 cases, normal in 2 cases. Urine β2-MG increased in 40 cases and normal in 39 cases. Urinary ultrasonography revealed 2 cases of renal cortical echo changes, 24 cases of kidney enlargement, and 1 left kidney shrinkage. Among 79 children, DMSA showed abnormal findings in 95 kidneys and CPDS, in 105 kidneys. The total sensitivity of CPDS was 69.4%, and the total positive predictive value was 62.8%. The sensitivity of CPDS under 6 months was 56.9%, which was 84.2% between 6 months to 1 year, and 94.4% from 1 to 3 years old, respectively. There was no significant correlation between CPDS levels and DMSA positive results. The abnormal rate of intermediate part in the kidneys was significantly lower than that in the upper and lower poles. Children with abnormal CPDS have a greater risk of renal scarring(p<0.05).

Conclusion

The sensitive of CPDS is highly age-related, it can as a non-invasive tool for assessment of acute pyelonephritis in infants, especially for infants more than 6 months old. CPDS is useful to be combined with DMSA to assess the APN of infants, for infants more than 6 months with febrile urinary tract infections, CPDS is the first recommendation, and followed by DMSA six months later to assess renal scar formation. For those less than 6 months, the DMSA assessment is still the preferred choice.

Urology & Nephrology

Color and power doppler sonography

99mTc-dimercaptosuccinic acid scintigraphy

Acute pyelonephritis

children

Kidney

Urinary tract infection（UTI) is a common disease in children. The difficulty in the management of UTI in children, and especially in infants, is failure to establish the diagnosis properly in the first place. Although most of the patients with good prognosis, acute pyelonephritis (APN), if not be treated promptly, can lead to permanent renal scar formation, which is an important cause of chronic renal failure in young people. Therefore, it's important to identify APN early and give it positive treatment ^[1]. However, the accurate diagnosis of APN in children still quite difficult on the basis of clinical and laboratory findings alone^[2,3].

Since 1972, The technetium 99m dimercaptosuccinic acid (DMSA) has been shown to be sensitive and specific for the diagnosis of APN^[4] and considered to be the gold standard for diagnosing APN at present, but there are still many disadvantages, for example, quite a few hospitals have not carried out this inspection, and which is radiation and expensive. It is clinically desirable to have a simple, inexpensive and non-radiative alternative method to help early identification and follow-up of children with APN.

Previous studies have shown that color and power doppler sonography (CPDS) can be used to evaluate renal cortical blood flow and contribute to the diagnosis of APN^[5,6], and compared the diagnostic difference between CPDS and DMSA in children with APN^[7-12]. Some studies believe that doppler ultrasonography can as a predictive tool for permanent kidney damage following acute pyelonephritis^[13], Others disagree^[14,15].

Most of the above studies focus on whether the CPDS can instead of DMSA for the diagnosis and follow-up of APN. but in our opinion, it is more important to make full use of their respective advantages, but not just replacement. To this end, we evaluated the new role of CPDS in the application of APN in infants by prospective combined use of CPDS and DMSA.

Study population

Participants: From June 2016 to Jan 2019 were admitted to the Yuying children's hospital affiliated to wenzhou medical university and clinically diagnosed with acute pyelonephritis, including 52 males and 27 females, age range 1 month to 3 years old. The diagnosis of APN is based on a combination of laboratory findings and typical clinical features, including high-grade fever (＞38.5℃), urinary tract infection (UTI) , and and elevated blood leukocytes or C-reactive protein (CRP) ^[16].

Inclusion criteria: Age less than 16 years old and all meet the diagnostic criteria for clinical APN.

Exclusion criteria: congenital structural anomalies of the urinary system.

Data collection

All patients underwent urinary routine, mid-stage urine culture, urinary β2 microglobulin (β2-MG), urinary N-acetylglucosaminidase (NAG), blood routine test, C-reactive protein (CRP), renal function, blood electrolyte, urinary ultrasonography (USG), CPDS and DMSA examination. All 92 patients underwent both CPDS and DMSA within 48 hours of hospitalization. If DMSA is abnormal, the second DMSA will be performed again after half a year.

The CPDS was operated by a senior ultrasound physician and was unaware of the results of the 99mTc-DMSA test. CPDS was performed using the Siemens Sequoia 512 scanner,with a 8–14 MHz(for children less than 3 months) and 2.5–4 MHz(for children more than 3 months) curved-array transducer.The children were placed in the lateral position, the kidney was examined by the lumbar section, the long diameter and thickness of the kidney were measured, and the probe was rotated 90 degrees to obtain the short axis section. The 99mTc-DMSA examination was performed by a senior doctor of ECT in our hospital and was unaware of the results of CPDS.

Result judgment: An abnormal manifestation of CPDS is the presence of partial or total perfusion defects in a region of the renal cortex. Each kidney was divided into three zones: upper pole, midzone, and lower pole. The presence of an area of decreased or absent flow was considered abnormal(The renal cortical perfusion was observed and graded. Grade III was cortical without perfusion, grade II was cortical venous perfusion defect, grade I was cortical. insect-like blood flow perfusion defect, normal non-perfused perfusion defect). The abnormal manifestation of DMSA is radioactive sparsity in a certain area of the renal cortex. According to the degree of sparseness, it is divided into the following four levels: normal, mild, moderate, and severe; also labeled as N,Ⅰ,Ⅱ and Ⅲ, respectively.

Statistical analysis

Comparisons between CPDS or DMSA findings were performed using Mann-Whitney nonparametric tests. The diagnostic values (sensitivity, specificity, predictive values, and accuracy) of CPDS and DMSA were assessed with contingency tables.

Comparison of general conditions of children

All 79 patients with high-grade fever and met the APN diagnostic criteria. The peripheral blood routine showed elevated white blood cells in 75 cases, normal in 4 cases, C-reactive protein (CRP) increased in 77 cases, normal in 2 cases. Urine β2 microglobulin (β2-MG) increased in 40 cases and normal in 39 cases. Urine N-acetylglucosaminidase (NAG) was elevated in 27 cases and normal in 52 cases. Renal function, albumin, and blood electrolytes were normal in all the patients. Urinary ultrasonography revealed 2 cases of renal cortical echo changes, both located in the upper pole of the kidney, 24 cases of kidney enlargement, and 1 case of left kidney shrinkage. The CPDS and DMSA inspections are shown in Table 1.

Comparison of CPDS and DMSA results in children

Among 79 children（158 kidneys）, 110 kidneys had abnormal DMSA and 122 had abnormal CPDS (see Table 1). The sensitivity of CPDS was 69.4% and the specificity was 38.1%. The positive predictive value of CPDS was 62.8%, and the negative predictive value was 54.7%. (See Table 1).

Table 1: Comparison of CPDS and DMSA results in children

Group DMSA + DMSA - Total

CPDS + 66 39 105

CPDS - 29 24 53

Total 95 63 158

+, Positive; -, negative.

Comparison of CPDS and DMSA results in children with different age

The sensitivity of CPDS detection was lower in children younger than 6 months of age, and the sensitivity increased with age. The sensitivity of CPDS was 56.9%(group 1), 84.2%(group 2) and 94.4%(group 3). The positive predictive value of CPDS was 63.4%(group 1), 59.2%(group 2) and 65.4%(group 3). (See Table 2).

Table 2: Comparison of CPDS and DMSA results in children of different age groups

group 1（<6M） group 2（6M ～ <1Y ） group 3（1Y ～ <3Y）

DMSA DMSA DMSA

groups Ⅲ Ⅱ Ⅰ N Ⅲ Ⅱ Ⅰ N Ⅲ Ⅱ Ⅰ N

CPDS Ⅲ 2 10 1 7 2 2 2 6 4 4 1 2

CPDS Ⅱ 0 3 2 7 1 1 4 2 0 1 0 3

CPDS Ⅰ 0 9 6 5 1 2 1 3 1 5 1 4

CPDS N 2 13 10 15 0 2 1 4 0 0 1 5

Total 4 35 19 34 4 7 8 15 5 10 3 14

Comparison of abnormal examination results of different kidney parts

There was no significant correlation between CPDS levels and DMSA positive results. The abnormal rate of Intermediate part in the kidneys was significantly lower than that in the upper and lower poles (See Table 3).

Table 3: Comparison of results of different kidney sites (part 1)

Left kidney upper middle lower

groups DMSA + DMSA - Total DMSA + DMSA - Total DMSA + DMSA - Total

CPDS + 24 15 39 5 15 20 20 19 39

CPDS - 17 23 40 7 52 59 16 24 40

Total 41 38 79 12 67 79 36 43 79

Table 3: Comparison of results of different kidney sites (part 2)

Right kidney upper middle lower

groups DMSA + DMSA - Total DMSA + DMSA - Total DMSA + DMSA - Total

CPDS + 19 20 39 1 6 7 11 20 31

CPDS - 11 29 40 5 67 72 15 33 48

Total 30 49 79 6 73 79 26 53 79

APN is common in infants but with a large clinical risk. It may lead to permanent renal scar formation, if its not recognized in time and effective antibiotic treatment. Studies have shown that the incidence of renal scar can reach 64% and a considerable number of cases therefore progress to ESRD. From clinical observation, the biggest problem facing the current urinary tract infection is not the treatment, but whether it can be diagnosed early and at the same time avoid the damage caused by over-diagnosis. Therefore, it is important to assess APN early and treat it effectively in a timely manner. However, our data showed that part of the patients had no abnormal increase in white blood cells, CRP, and urinary enzymes. Therefore, it is especially important to identify APN by combine imaging tests.

The DMSA, with high sensitivity and specificity, has been used for the detection and localization of APN inflammation for long time and been became the gold standard for the current diagnosis of APN. Although DMSA is widely used in clinical practice, we still have to face lots of problems, such as the presence of radioactivity, the price is relatively expensive, and its sensitivity is not 100%, DMSA negative do not completely rule out APN. Except for the possibility of false negatives in DMSA itself, We found that some results really difficulty to be interpretated.In this study, 7 patients had typical clinical manifestations of APN, urine culture was positive, peripheral blood leukocytes and CRP were significantly increased, clinical diagnosis of APN was clear, but DMSA results were negative. A similar finding was found in previous studies by Hitzel A et al^[7]. which suggesting that there is still a certain rate of missed diagnosis if just depending on the of DMSA. Therefore, the difficulty in reading DMSA is also an important cause of false negatives. Early diagnosis of APN is still difficulty in clinical practice.

Various types of renal vascular and renal parenchymal lesions are closely related to changes in intrahepatic arterial hemodynamics ^[17]. CPDS is developed on color Doppler technology and is superior to color Doppler flow imaging in showing sensitivity and continuity of blood flow. Because this test is more sensitive to low-speed blood flow, it reflects the integrated power from the reflected echo of the renal parenchyma ^[9]. Bude et al ^[18]first reported the imaging ability of PDS on renal cortical blood perfusion. Since then, many studies have used PDS to study the effects of various kidney diseases on renal blood flow ^[15,19-21]. Previous studies have shown that CPDS can contributes to the diagnosis of APN, Anne Hitzel^[7] has shown that although the predictive value of CPDS for renal scar is not high, the results of CPDS and DMSA are consistent in 81% of APN kidneys, suggesting that it is better clinical application value. In view of the fact that the study did not cover all children and did not involve the exploration of specific parts of the infection, it is necessary to further explore.
To further assess the value of CPDS in the early diagnosis of APN in children of infants, and to clarify the sensitivity and specificity of CPDS for detection of different parts of the kidney, A comparative analysis of CPDS and 99mTc-DMSA renal static imaging was implemented and so as to explore the value of CPDS in the diagnosis of APN in infants..

Our study showed that those patients, whose age more than 6 months, with negative CPDS had a low probability of DMSA positivity and had a good agreement with the latter. Two double-blind controlled studies have also suggested that the specificity of CPDS for the diagnosis of APN is 85% to 95%, and the sensitivity is 55% to 75%, which is highly consistent with DMSA examination ^[5,8]. The data showed that the sensitive of CPDS is highly age-related. With the increase of age, the sensitivity of CPDS gradually increased, the sensitivity of CPDS was less than 60% in the group less than 6 months old, but increased to 84.2% and 94.4% in the group 2 and group 3,respectively. which may be related to a change in kidney blood flow caused by crying in an unsedated situation. In order to avoid deviations in the test results, infants should be tested in a quiet state.
The above findings suggest that in infant older than 1 year, there is a more reliable option for screening infants with suspected APN using CPDS. For infants in the age group less than 6 months, the sensitivity and the specificity of CPDS are poor. It is not suitable for diagnosis.
At present, if the first DMSA inspection positive, the second DMSA is routinely reviewed 6 months after infection to help determine whether there is renal scar formation, which causes certain damage to the patients and lots of family refuse to do. In addition, since DMSA cannot judge abnormalities caused by recent APN or previous occult APN infection, so its positivity does not necessarily support APN diagnosis. Therefore, we do not recommend the use of DMSA in the acute phase of the disease. We believed that CPDS can be used for help the diagnosis of APN in the early stage of the disease in those patients older than 6 months. DMSA testing should be carried out 6 months latter after the infection, so as to effectively understand the renal damage of APN and the incidence of renal scar, and then determine the prognosis of the disease.

Our study also found that there was no significant correlation between CPDS abnormal level and DMSA positive results, which was inconsistent with our pre-expected results. We also observed that the location of renal abnormalities found by CPDS and DMSA is not the same. This may be related to the difference between the blood supply abnormalities and the infected sites, and does not rule out the different stages of the disease. The effect suggests that there is complementarity between the two image inspection in clinical diagnosis of APN.

The pathophysiologic mechanism responsible for CPDS imaging abnormalities are focal ischemia due to vascular compression induced by interstitial edema^[22]. While the uptake of 99mTc-DMSA by the renal parenchyma is dependent on the glomerular perfusion and the transport function of the proximal tubule cell membrane. Since the detection mechanism of CPDS and DMSA is different when which be used to detect APN. DMSA abnormalities can not be judged from blood supply abnormalities or renal tubular epithelial cell damage, while CPDS can determine the blood supply of the kidneys, so these two methods have good complementarity. It is not necessary to focus on replacing DMSA with CPDS in clinical practice, but to synergistically utilize their respective advantages to improve the clinical APN assessment level. There are still many questions to be explored in this field. For example, the apparent abnormality of CPDS confirms the lack of blood supply to the kidneys, does it suggest that there is a risk of further damage to the renal tubular epithelial cells, and which will leading to an increased probability of renal scar formation? In addition, if the CPDS is normal and the DMSA is abnormal, whether to prompt the renal tubular epithelial cells already exist serious damage? Further discussion on these issues will undoubtedly help to improve the current clinical assessment level for infants with APN.

In conclusion, the sensitive of CPDS is highly age-related, it can as a non-invasive tool for assessment of acute pyelonephritis in infants, especially for infants more than 6 months old. CPDS is useful to be combined with DMSA to assess the APN of infants, for infants more than 6 months with febrile urinary tract infections, CPDS is the first recommendation, and followed by DMSA six months later to assess renal scar formation. For those less than 6 months, the DMSA assessment is still the preferred choice.

Acknowledgements

The authors wish to thank the staff of the department of Nephrology，Rheumatology，Ultrasonics for their important contributions. The results presented in this paper have not been published previously in whole or part。

Consent for publication

Not applicable

Funding

No funding was received for this work.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author’s contributions

MGC participated in research design, data collection, data analysis and writing of the article. YY participated in data collection and operating ultrasound examination of all patients. QY participated

in research design and writing of the article. JQZ participated in data collection and writing of the article. XHY, participated in data collection and writing of the article. WJZ participated in research design, data collection, data analysis and writing of the article. All authors read and approved the final manuscript.

Ethics approval and consent to participate

This retrospective study was reviewed and approved by the Institutional Ethics Committee from the The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University，China. As this was a retrospective study, written consent to participate from the study subjects was not required.

Competing interests

The authors declare no conflicts of interest or competing interests.

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Author details

¹Department of Rheumatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China

²Department of Nephrology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China

³Department of Ultrasonics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China

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New strategy of color and power doppler sonography combined with DMSA in the assessment of acute pyelonephritis in infants

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