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ORIGINAL ARTICLE
Adv Biomed Res 2022,  11:89

Kidney failure in children with Wilms tumor: A study based on urine analysis and ultrasound


1 Department of Biochemistry and Hematology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
2 Department of Basic and Laboratory Sciences, Khomein University of Medical Sciences, Khomein, Iran
3 Clinical Research Development Center of Amir Kabir Hospital, Arak University of Medical Sciences, Arak, Iran
4 Department of Pediatric Nephrology, Arak University of Medical Sciences, Arak, Iran
5 Clinical Research Development Center of Aliasghar Hospital, Iran University of Medical Sciences, Tehran, Iran

Date of Submission20-Nov-2021
Date of Acceptance27-Dec-2021
Date of Web Publication29-Oct-2022

Correspondence Address:
Dr. Vahid Falahati
Clinical Research Development Center of Amir Kabir Hospital, Arak University of Medical Sciences, Arak
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/abr.abr_367_21

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  Abstract 


Background: Renal insufficiency is one of the inevitable complications in patients with Wilms tumor (WT). The purpose of this study was to assess the renal function in children with WT at baseline and every 3 months to 2 years.
Materials and Methods: In a descriptive-analytical study from 2018 to 2020, 48 children with WT were included in the study. Urine creatinine (UCr), serum calcium (SCr), blood pressure (BP), estimated glomerular filtration rate (eGFR), and urinary protein (UPro) were evaluated at baseline and every 3 months during the study. Spot UCa/UCr and spot UPro/UCr ratio were calculated. Kidney ultrasonography was used in all patients. Independent Sample t-test and Chi-square tests were utilized to compare age and sex, respectively.
Results: The mean age of patients at follow-up was 7.3 years. There was no significant difference in mean UCr, SCr, eGFR, 24-h UPro, UCa/UCr ratio, and spot UPro/UCr ratio at baseline and end of study (Pbaseline > 0.05, Pend of study > 0.05). Analysis of kidney size showed a statistical association with tumor stage (P < 0.05). Comparison of the kidney size in patients showed that there is a statistically significant difference (P < 0.0001) at baseline and end of the study.
Conclusion: This study showed that as WT progressed, the size of the kidneys increases without any renal insufficiency. Therefore, it seems that urinalysis of patients with WT along with sonography is necessary to determine renal insufficiency and the use of ultrasound alone to determine kidney insufficiency is not recommended.

Keywords: Child, renal insufficiency, Wilms tumor


How to cite this article:
Ghasemi A, Ghaffari K, Gohari A, Eghbali A, Yousefichaijan P, Falahati V. Kidney failure in children with Wilms tumor: A study based on urine analysis and ultrasound. Adv Biomed Res 2022;11:89

How to cite this URL:
Ghasemi A, Ghaffari K, Gohari A, Eghbali A, Yousefichaijan P, Falahati V. Kidney failure in children with Wilms tumor: A study based on urine analysis and ultrasound. Adv Biomed Res [serial online] 2022 [cited 2022 Dec 3];11:89. Available from: https://www.advbiores.net/text.asp?2022/11/1/89/359888




  Introduction Top


Wilms tumor (WT) is the most common renal malignancy and is one of the most common abdominal tumors in children, also known as nephroblastoma or renal embryoma. The prevalence of WT in children under 15 years of age is 1 in 100,000 and accounts for about 5% of all childhood malignancies,[1] which can emerge as a simple nodule, unilateral multifocal lesion, and bilateral tumors.[2] Bilateral tumors are found in 5%–14% of WT patients.[3]

Several studies had shown that aging independently increases the risk of nonmetastatic WT recurrence. The age of fewer than 2 years is recognized as a pleasant factor in prognosis and the age of more than 4 years is known as the factor of poor prognosis in children.[2],[4]

The clinical symptoms of WT in infants are as same as signs in older children and were usually diagnosed by a randomly identified abdominal mass; however, some patients with kidney tumors at this age may also present hematuria, hypertension, and metastatic symptoms such as hydrocephalus or a mass on neonatal ultrasound.[5] The survival of the patients with WT had increased drastically from 30% in previous years to 90% survival of 5–7 years in the current years.[6] As the number of children rescued increases, the problem of delayed toxicity from treatment is significant. The application of radiation therapy is one of the significant factors causing long-term complications.[7]

In treated patients, as long as nephrectomy is an important part of the treatment of the disease. Chronic kidney disease is a unique potential complication and the quality of life after treatment depends on kidney function. Although end-stage renal disease is uncommon in nonsyndromic unilateral tumors; but studies have shown a decrease in glomerular filtration rate (GFR) in the long term in these patients.[8]

Maintaining normal renal function in patients with bilateral WT is essential for hemodialysis and prevention of renal dysfunction, but this procedure is very complicated in tumors larger than 4 cm in diameter and multifocal nephroblastoma. Furthermore, a dramatic decrease in the number of nephrons is associated with the development of hypertension and progressive renal failure, known as the Brenner-Barker hypothesis.[9] Therefore, a better understanding of the late effects of WT disease is essential to increase patient survival and quality of life. Evaluation of late complications of tumors in children, such as risk factors and prevalence, are important topics for risk management and selecting appropriate treatment strategies. The purpose of this study was to assess the renal function in children with WT at baseline and every three months to 2 years.


  Materials and Methods Top


Patients

In a descriptive-analytical study from 2018 to 2020, 48 children with WT were selected at the Amir-Kabir Hospital, Arak, Iran, and have a minimum follow-up of 2 years. All ethical principles were observed according to the ethical protocol approved by the Research Ethics Committee of Arak University of Medical Sciences (IR.ARAKMU.REC.1397.310) and the criteria for excluding the study included conscious dissatisfaction, unwillingness to continue to participate in the study. After obtaining informed consent children aged 2–8 years were selected and included in the study. The study was done according to the Declaration of Helsinki.[10] One of the most important treatment and prognostic criteria for patients with WT are the grade. WT grading criteria are not based on biological and molecular markers but the anatomic extent of the tumor. Patients grading was determined as described elsewhere.[8] Based on the stage, patients were classified into 4 categories (WT-I, WT-II, WT-III, and WT-IV).

Anthropometric data

Demographic and clinical information of patients were initially recorded. Weight was measured using the standard methods as recommended by Lohman.[9] The error due to heavy clothing and shoes in calculating the weight of patients was calculated. Height was calculated to the nearest 0.1 cm using commercial stadiometers available in the market (Leicester Height Measure, Invicta Plastics Ltd., UK). To measure height, conditions such as removing the shoes, the body is fully stretched, upright without bending, arms stretched along shoulder width, face directly in front of the researcher so that the Frankfort plane was considered. Body mass index (BMI) was measured using Quetelet's equation (weight in kg/height in m2). BMI was calculated based on Z-score using the WHO method.[11] Waist circumference (WC) was measured to the level of umbilicus using a measuring tape, by measured midway between the lower surface of the ribs and the iliac crest in a horizontal line. Hip circumference (HC) was measured at the widest part of the hip. Three measurements to the nearest 0.1 cm were recorded for each WC and HC. Then, the average of the measurements was calculated. All measurements were calculated with the same tape and without clothes. The weight-to-height ratio (WHtR) was obtained by dividing the mean WC by the mean height. The waist-to-hip ratio (WHR) was obtained by dividing the mean WC by the mean HC.

Blood pressure (BP) was measured 3 times at 1-min intervals after the patients had rested for 10 min in a sitting position. A suitable cuff was used based on the size of the patient's arm to prevent false results. The mean values of the first two readings for systolic BP (SBP) and diastolic BP (DBP) were calculated separately. If the difference in the first two readings was more than 10, the average of the two close readings was calculated. SBP and DBP were measured by a researcher on the right arm using a standard sphygmomanometer according to the World Health Organization (WHO) recommendations.[12] Hypertension is defined as average SBP and/or DBP that is greater than the 95th percentile for gender, age, and height.[13]

Evaluation of renal function

Various laboratory tests were performed to assess kidney activity. Spot urine and 24-h urine sample were collected from patients. Both first morning and random samples are acceptable, although first morning samples are preferable if possible. Urine creatinine concentration (UCr), urine calcium concentration (UCa), and urine protein (UPro) were determined and recorded at the baseline and every three months during the study for renal function evaluating by Kinetic Jaffe reaction, the colorimetric method with methylthymol blue, and turbidimetric method, respectively, using an Auto Analyzer Roche/Hitachi Modular DPP. Five milliliter of blood samples were collected to evaluate serum creatinine (SCr). The standard range of SCr was classified according to age and sex.[14]

Then spot UCa/UCr ratio and spot UPro/UCr ratio were calculated by dividing the UCa to the UCr and the UPro to the UCr, respectively. A normal reference interval for the UCa/UCr (mg/mg) ratio is <0.14.[15] Hypercalciuria was considered as UCa/UCr >0.25 mg/mg. However, the upper limit of UCa/UCr is controversial for accurately determining hypercalciuria.[16] Spot UPro/UCr ratio >0.7 mg/mg is defined as proteinuria.[17]

Hemoglobin concentration (Hb) was measured in potassium EDTA using standard methods. Estimated GFR (eGFR) was calculated using the conventional Schwartz equation (κ ×height of the child in cm/serum creatinine concentration in mg/dl, κ=0.55 for children aged 2–12 years).[18]

Kidney ultrasonography was used in all patients to determining kidney size. Patients were evaluated in the position of supine decubitus. Two well-trained radiologists performed an ultrasound examination of the kidneys using a standard B-mode gray-scale ultrasound machine (EUB-8500, Hitachi Medical Corp., Tokyo, Japan), with a 7.5–13.0 MHz frequency probe. At maximal length points, kidney size was measured. Standard laboratory methods were used to measure the desired blood and urine parameters. Before and during the study, all equipment used for the measurement was calibrated. Each measurement was performed three times by experienced and trained members of the research team.

Statistical analysis

Data were expressed as mean ± standard deviation (SD). The analysis was performed applying GraphPad Prism 6.0 (GraphPad Software, San Diego, CA). Independent Sample t-test and Chi-square tests were utilized to compare age and sex, respectively. Pearson correlation test was used to identify the correlations for continuous variables. A cumulative hazard of renal dysfunction (%) was reported for patients with WT. To evaluate renal dysfunction, UPro excretion was calculated. The significance level of the P value was considered less than 0.05.


  Results Top


A total of 48 patients with a mean age at diagnosis of 5 ± 3.2 years (range 2.6–9.4 years) were enrolled and selected to participate in the study. The mean age of patients at follow-up was 7.3 years (range 3.7–11.1 years), mean follow-up time was 1.9 years (range 0.5–2.0 years). Of the 48 WT included, 28 (58.3) were female, 20 (41.7) were male. The right kidney was affected by the tumor in 52% of cases and the left kidney in 48% of cases. Ten patients (20.8%) had grade I (WT-I) of the disease, 21 (43.7%) had grade II of the disease (WT-II), 9 (18.8%) had grade III of the disease (WT-III), and 8 (16.7%) had grade IV of the disease (WT-IV). None of the patients had a urinary tract infection at the time of evaluation.

Demographic and anthropometric characteristics are shown in [Table 1]. An estimated cumulative hazard of renal dysfunction in patients was noticeably increased beyond 2 years of follow-up [Figure 1]. Analysis of BP in the present study showed that overall, 4 of the patients (8%) were found to have abnormal SBP and 2 (4%) abnormal DBP, based on the consensus guidelines for diagnosis of hypertension.[19] However, no significant differences were observed in systolic and diastolic BP at baseline and end of study (P > 0.05).
Figure 1: The cumulative hazard of renal dysfunction in patients with Wilms tumor

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Table 1: Demographic and anthropometric characteristics of patients with Wilms tumor

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There was no significant difference in mean weight, height, WC, HC, WHR, WHtR, and BMI at baseline and at the end of the study (Pbaseline > 0.05, Pend of study > 0.05).

In total, the mean ± SD of UCr, SCr, eGFR, and 24-h UPro were 139.3 ± 1.05 mg/dl, 1.9 ± 0.05 mg/dl, 110.8 ± 1.2 mL/min/1.73 m2, and 320.9 mg/day, respectively, at baseline. No significant differences were observed in UCr, SCr, eGFR, and 24-h UPro between different grades at baseline (P > 0.05), but there was a significant difference in UCr and 24-h UPro between grade 1 and grade 4 of the disease at baseline and end of study (P < 0.05). In total, the mean ± SD of UCr, SCr, eGFR, and 24-h UPro were 141.5 ± 3.16 mg/dl, 1.9 ± 0.08 mg/dl, 110.7 ± 1.3 mL/min/1.73 m2, and 401.9 mg/day, respectively, at the end of the study. No significant differences were observed in UCr, SCr, eGFR, and 24-h UPro between different grades at the end of the study (P > 0.05). There was no significant difference in mean UCr, SCr, eGFR, 24-h UPro, UCa/UCr ratio, spot UPro/UCr ratio, and Hb level at baseline and end of study (Pbaseline > 0.05, Pend of study > 0.05). There was a trend toward higher UCr concentration and 24-h UPro along with increasing the grades of the tumor, so that UCr concentration and 24-h UPro in WT-IV were more than WT-I, WT-II, and WT-III [Table 1].

Thirty-nine patients (81.2%) at baseline and 41 patients (85.4%) at the end of the study had a high spot UPro/UCr >0.7 mg/mg which indicates proteinuria. Patients with higher grades had more severe proteinuria (data not shown). No significant differences were observed in spot UPro/UCr ratio between grade 1 and grade 4 of the disease at baseline (P = 0.074) and end of study (P = 0.132).

Forty-one patients (85.5%) at baseline and 42 patients (87.5%) at the end of the study had a high UCa/UCr ratio which indicates hypercalciuria. Patients with higher grades had more severe hypercalciuria (data not shown). There was a significant difference in UCa/UCr ratio between grade 1 and grade 4 of the disease at baseline (P = 0.024) and end of study (P = 0.038).

Analysis of kidney size showed a statistical association with tumor grade (P < 0.05). The size of the kidney in WT-IV was larger than other grades at baseline and after follow-up [Table 1]. Comparison of the kidney size in patients showed that there is a statistically significant difference (P < 0.0001) at baseline and duration of the study [Figure 2]. Therefore, there was a significant difference in kidney size between grade 1 and grade 4 of the disease at baseline (P = 0.048) and end of study (P = 0.047).
Figure 2: Analysis of kidney size in patients with Wilms tumor at baseline and after follow-up

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  Discussion Top


This study revealed that the most frequent grade of the disease in children was WT-II. Our result showed that BMI, systolic-diastolic BP, urine protein, urine Cr, serum Cr, urine Ca, serum Ca, UCa/UCr ratio, Hb level, and eGFR in baseline and during the study did not change significantly. However, the kidney size increased significantly in patients. In the other words, patients with WT are greatly predisposed to the increase of kidney size over time and it seems that the first renal symptom in these patients is an oversized kidney. It can be effective in the patient's follow-up with WT who are being treated. Given that patients with WT are at risk for renal impairment during treatment with nephrectomy, chemotherapy, or radiation, it is important to find a marker to indicate a renal function in these patients. In this study, we showed that as WT progressed, the size of the kidneys increases without any renal dysfunction. Therefore, it seems that urinalysis of patients with WT along with sonography is necessary to determine renal dysfunction and the use of ultrasound alone to determine kidney dysfunction is not recommended.

In a study about evaluating renal function in 75 patients with WT, the authors found that most patients were in grades I and II and none of the patients had eGFR less than 60. They also showed that 6.7% of patients had hypertension, and patients with WT who had undergone surgery and had not received nephrotoxic chemotherapy or radiotherapy were less likely to have renal dysfunction. However, monitoring is necessary to assess renal function (to identify a limited group of patients with impaired renal function).[20]

Mullen et al. evaluated the role of sonography in the diagnosis of WT recurrence in patients with WT recurrence and found that follow-up using regular sonography showed major abdominal recurrences.[21]

Monastyrskyi et al. evaluated the changes in kidney size after nephrectomy in mice and found that animals undergoing nephrectomy had a significant increase in kidney size.[22] In our study, we found that based on sonography, the kidney size increased significantly during the study, but no changes in the variables related to renal function including eGFR, creatinine, urine Ca/Cr, and urine Pr/Cr were seen. Therefore, according to the study by Monastyrskyi et al. in which an increase in kidney size had been seen following nephrectomy and also because the main treatment is involved in patients with WT surgery and renal nephrectomy, it seems that the use of ultrasound and kidney size assessment of all patients during the disease in the diagnosis possible renal dysfunction has no role and due to the increased response in kidney size, ultrasound is not a suitable method to follow-up patients. However, to investigate the relationship between increased kidney size and the occurrence of renal dysfunction in patients with WT, more studies are needed over a long time.

Furthermore, several studies have shown an intimate relationship between kidney size and its function, though, concerning the results of our study, there is no relationship between sonographic findings and renal dysfunction in patients with WT.

In a study, Antoniewicz et al. evaluated renal function (serum level of creatinine and eGFR) in patients (mean age ± SD, 62.2) with kidney tumor who had undergone surgery and found that from 3 months after surgery, the serum level of creatinine increased, but the level of eGFR decreased.[23] However, in our study, the mean of creatinine and eGFR did not change significantly during the study. One of the reasons for the difference between the results of the present study and the above study could be the difference in the age range of the patients studied. Furthermore, differences in tumor type can be another reason for differences in the results of the two studies. Due to the few studies on renal dysfunction in patients with WT, there could not compare the results of the variables in patients with WT with the other studies.


  Conclusion Top


The present study showed that as WT progressed, the size of the kidneys increases without any renal dysfunction. Therefore, it seems that urinalysis of patients with WT along with sonography is necessary to determine renal dysfunction and the use of ultrasound alone to determine kidney dysfunction is not recommended.

Acknowledgment

The authors acknowledge the staff of the Blood and Oncology Department of Amirkabir Hospital, Arak, Iran.

Financial support and sponsorship

This study is under the Arak University of Medical Sciences grant with Grant No. 3167.

Conflicts of interest

There are no conflicts of interest.



 
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