The development of the human renal-
adrenal system between 10 and 24 weeks of
gestation
Student name & number: Fionnuala Lorrez, 11607173
Date: 25th of June 2020
University & bachelor: University of Amsterdam; Faculty of Natural Sciences,
Table of Contents
Abstract ... 2
Introduction ... 3
Materials & Methods ... 5
Results ... 9
Discussion ... 22
References ... 24
Appendix ... 26
Abstract
The renal-adrenal system starts developing early during embryogenesis. Abnormal development of these structures can result in congenital anomalies. Previously, renal-adrenal development during the embryological period has been presented in the 3D Atlas of Human Embryology, leading to a wealth of novel insights. However, little is known about the late organ development in the fetal period. Therefore, a study has been created to understand the normal growth of the systems between 10-24 weeks gestation. This was done with an empirical study; utilizing fetuses from the fetal biobank of Amsterdam UMC using micro-CT imaging and a systematic review. The images were imported, and 3D images were created in Amira (2019.4). From these models, the length, volume and position were obtained. Data from both sub-studies were compared. The search in PubMed released 10 included articles for the systematic review and 11 fetuses were obtained for the empirical data with gestational ages between 13+5 and 23+3 weeks. The length and volume showed an exponential correlation with the gestational age, and the position of the organs relative to the spine, move minimally. However, the sample size of this study is small, and a larger sample size is therefore a recommendation for future research.
Introduction
Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) comprise of a wide range of structural malformations resulting in defects in the morphogenesis of the kidneys and the urinary tract (Capone et al., 2017). Malformations can appear either uni- or bilaterally and when combined with multiple anomalies, the understanding of collaborated malfunctions, become more complicated (Pope et al., 2018). Three to six children in a 1000 were affected by CAKUT in the 80’s (Schulman et al., 1993), this number has now increased to ten in 1000 newborns and is therefore the most common congenital defect (Genetics Home Reference, 2020). CAKUT is responsible for 20% of the birth defects (Loane et al., 2011) and 7% of the end-stage renal diseases worldwide (Sanna-Cherchi et al., 2009). Kidneys are assessed routinely during the midtrimester anomaly scan. Through the routine midtrimester scan, about 60% of CAKUT are diagnosed prenatally, providing parents with important diagnostic information upon which they can make an informed decision about the hospital where the delivery should take place, postnatal treatments, as well as pregnancy termination (Hindryckx & de Catte, 2011). However, assessment of the adrenal glands is not part of this routine examination (Salomon et al., 2011). Some anomalies regarding the adrenal glands have proven to be fatal postnatal. Congenital adrenal agenesis is a rare, but lethal, condition in which the adrenal glands fail to develop during the organogenesis. This condition is mostly associated with additional congenital anomalies. From the nine cases reported to date, congenital adrenal agenesis had been found through incidental post-mortem examination (D’Arcy et al., 2014), revealing that the adrenal glands were not scanned during the routinely second trimester ultrasounds.
Despite the kidneys and adrenal glands deriving from different embryonal backgrounds, due to the anatomical position of the adrenal glands above the kidneys, it is of interest to study the development of the organs in relation to one another. The most important function of the kidneys include regulation of the electrolyte balance; the homeostasis of water and ion content in blood, controlling waste removal, and hormone production (Donkelaar et al., 2014). Whereas the most important function of adrenal glands is the production of hormones and the regulation of the electrolyte balance (Donkelaar et al., 2014). Understanding the development of the kidneys and adrenal glands can lead to improvements in the prenatal detection of CAKUT and adrenal glands, such as congenital adrenal agenesis. Both are not or rarely detected with prenatal sonography and often remain undiagnosed until adulthood (Capone et al., 2017). Examples of CAKUT could be aided; such as uni- or bilateral renal agenesis (Saphier et al., 2000), compensatory renal hypertrophy and multicystic dysplastic kidneys (Glazebrook et al., 1993; Hill et al., 2000).
regression of the pronephros, mesonephros and the ductus mesonephricus (Felix, 1912). Although recent research led by de Bakker et al., (2019) has discovered that the pronephros is not detectable in human embryos, contrary to common belief. The metanephros, which will become the permanent kidney, develops late week four and early week five from the intermediate mesoderm together with the ureter (Donkelaar et al., 2014). Unlike most organs the majority of the relative kidney growth finds place during the late second and third trimester of pregnancy. The kidneys grow in absolute size after birth (Moore et al., 2016) with a decreasing rate up to seven months (Mesrobian et al., 1998). The suprarenal development starts in the sixth week with the migration of mesothelial cells, deriving from the intermediate mesoderm, forming the cortex, followed in week eight with the forming of the medulla, derived from the neural crest cells, and the descent to their definitive position above the kidneys (Donkelaar et al., 2014). The development of a fetus during the first 10 weeks of gestation has already been researched and made visually available by De Bakker et al., (2016). This leaves us to inquire how the kidneys and the adrenal glands develop between 10 and 24 weeks of gestation. Based on findings regarding the morphological growth of the renal-adrenal systems, it is expected that the adrenal glands move minimally and that the kidneys grow but remain in their current position starting from their development.
Earlier research has concluded that the renal parenchyma grows in a constant linear pattern (Hadar et al., 2012) and that the volume does not significantly differ between the right and left kidneys (Tedesco et al., 2008; Yu et al., 2000). Throughout the growth of the fetus, the volume and gestational age of the adrenal glands correlate well. Between 18 and 28 weeks of gestation, the weight of the adrenal glands multiplies by seven, with the left adrenal gland continually being heavier than the right adrenal gland. This suggests that the left adrenal gland is bigger in size overall than the right adrenal gland (Folligan et al., 2005). Some lacunae in research are the ratios between the renal-adrenal system during the development in terms of length and volume and the location of the renal-adrenal systems relative to the vertebrae.
The aim of this thesis is to study the morphological development of the renal-adrenal system, both individually, and relative to one another between 10 and 24 weeks gestation in healthy human fetuses. This will firstly be done with an empirical study followed by a systematic review. Fetuses donated through the Dutch fetal Biobank Project will be imaged using contrast-enhanced micro-CT to visualize renal-adrenal development. The kidneys and adrenal glands are further labelled in AMIRA (version 2019.4, Thermo Fisher Scientific, Hillsboro, OR) for the creation of 3D reconstructions and to allow for quantification of growth. In order to quantify normal renal-adrenal development, the
Materials & Methods
First, the empirical research enquiring about sample acquisition, -preparation, micro-CT scanning and the 3D reconstruction will be discussed. Secondly, the systematic review regarding the search strategy and selection, the data extraction and risk of bias, together with the data-analysis will be examined.
Empirical research
Sample acquisition
Fetuses that were obtained for this experiment were donated through the fetal biobank of the Amsterdam University Medical Centre (Amsterdam UMC), following pregnancy termination for non-medical reasons. Fetuses with no apparent malformations and no chromosomal abnormalities were included in the study. Both maternal and paternal written consent was acquired before the fetuses were donated. The protocols regarding the procurement are approved by the medical ethical committee of the Amsterdam UMC, ethical review number: METC 2016_285,#B2017369. Donated specimens were fully anonymized and handled with great care and respect.
Sample preparation
After acquirement, the fetuses were fixed with 4% paraformaldehyde (PFA) between two and seven days depending on fetal size. Once fixed, the fetuses were stored in 0.2% PFA to prevent external factors reducing the quality of the tissue.
Micro-CT scanning
After storage of three to four days, with a maximum of 40 days, the fetuses were stained by immersion in a 3.75% isotonic Lugol’s solution (1:2 iodine and potassium iodine) to prevent tissue shrinkage. They were rinsed, fixed and stabilized with 1.5% agarose to prevent motion artefacts during the scanning. Foetuses were scanned in the transversal plane with a Micro-CT or 3D non-invasively and non-destructive imaging, using a GE Phoenix v|tome|xm tomographer (General Electric, Wunstorf, Germany). The system contained two X-ray sources. A 240 microfocus tube with tungsten target was employed. X-rays were produced with a voltage of 180 to 210 kV and a current of 180 to 210 μA depending on fetal size. A 0-0.5 mm Copper filter was used to avoid beam hardening. The images from the fetus were recorded with a GE DXR detector array with 2024 × 2024 pixels (pixel size 200µm). The
detector was located within a reach of 815mm from the X-ray source. A single full scan consisted of 3000 projections over an angle of 360°. The 1st image was skipped of the full scan. The saved projections used in AMIRA, were an average of 3 images where every image is obtained over a period between 250-330 ms exposure time. GE reconstruction software (Wunstorf, Germany) was used to calculate the 3D structure via back projection.
Image labelling and 3D reconstruction
Following the scanning, the micro-CT images were imported into the AMIRA program, a specialized post-processing imaging software (2019.4 version). Here, the kidneys, kidney medulla, kidney pelvis, ureter and adrenal glands were labelled per slice with their respective own colors in the transverse plane. With help of the reconstruction software, the slices with the labelled organs were put together and represented in 3D.
Figure 1 - Transverse image from TOP10 (13 weeks and 5 days) of the kidneys (brown) and adrenal glands (green) in AMIRA.
Systematic review
Search strategy
For the systematic review, literature on the human kidneys and adrenal glands was acquired with the help of a search string and the database PubMed, using Boolean operators. There were no search limitations in terms of language or year of publication. The search string was made up of terms using ‘Medical Subject Heading’ (MeSH), which enables the search of certain vocabulary within the MEDLINE records and ‘Titles and Abstracts’ (Tiab) that uses multiple combinations of words and searches these in the title and abstract. The search string was made up of terms regarding: ‘kidney’, Figure 3 - Sagittal image from TOP10 (13 weeks and 5
days) of the kidneys (brown) and adrenal glands (green) with AMIRA.
Figure 2 - Coronal image from TOP10 (13 weeks and 5 days) of the kidneys (brown) and adrenal glands (green) in AMIRA.
‘adrenal gland’, ‘fetus’, ‘anatomy’, ‘human’, ‘development’ and ‘techniques’. For the complete search string see appendix A1.
Study selection
The results from PubMed were imported into Rayyan, a filtering programme for systematic reviews (Ouzzani et al., 2016). In this program, the following inclusion criteria were applied: fetal period (10 – 24 weeks of pregnancy) and organs of interest: kidneys or adrenal glands. Studies utilizing the following visualization techniques were eligible for inclusion: MRI, (micro-)CT, ultrasound and/or dissection. Exclusion criteria included: only animals, only the embryonic period, only unhealthy fetuses. After the rudimentary filtering, the abstracts were read and they were filtered into ‘included’, ‘excluded’ or ‘maybe’. Articles in ‘included’ were fully read and filtered again, whilst articles in ‘maybe’ were fully read and placed either in ‘excluded’ or ‘included’.
Data extraction
The data extracted from the articles regarded the renal and adrenal gland lengths and volumes. The articles which had a relevant content, were split into two categories, ‘relevant for qualitative data-analysis’ and ‘relevant for the quantitative data-data-analysis’.
Risk of bias
A modified Cochrane Risk of Bias checklist (Higgins et al., 2011) for the assessment of methodological quality of included studies was used. In this checklist, the specimen age and number, the inclusion criteria, visualization techniques, the analysis and the results separated per age group were assessed. This checklist had to be ticked with ‘yes’, ‘no’ or ‘unclear’. Studies that scored one or more ‘no’ or two or more ‘unclear’ were regarded as having a high risk of bias and were excluded from the data-analysis. See Appendix A2 for the format.
Data-analysis
Due to a variety of techniques and methods applied by studies to quantify growth, it was decided to present data obtained from studies in a descriptive manner rather than performing a formal meta-analysis. The parameters were obtained and then compared descriptively against the empirical
Results
First, the empirical research results will be discussed regarding volume, length and position. Afterwards the results of the systematic review will be discussed. The data from both the systematic review and the empirical research are later combined.
Empirical research
In this research, 11 fetuses were utilized of whom seven were male and four female, between the gestational ages of 13+5 days and 23+3 days. See Table 1 for the characteristics. The kidneys and adrenal glands were visualized and labelled with an average amount of 300 micro-CT slices per fetus. The labelled organs were then visualized in 3D. The 3D models were used to calculate the volume, length and position. The measurements can be found in appendix A3.
Table 1 - Characteristics of the fetuses obtained from the fetal biobank from the Amsterdam UMC, location AMC.
Fetus Gender Gestational age
(weeks+days)
Total body volume (ml) Additional comments
TOP10 F 13+5 24.37 /
TOP44 F 14+5 52.18 /
TOP62 M 15+0 37.41 Hemofelia B
TOP29 F 16+2 70.25 Genetic abn. (no
morphological anomalies expected) TOP27 M 17+0 119.13 Hemofelia A TOP37 F 19+0 217.37 / TOP56 M 19+1 251.72 / TOP24 M 21+1 396.76 Ghnato-cheilo-palatoschisis (normal karyotype) TOP23 F 21+1 345.01 /
TOP9 M 21+5 355.18 Distended bowel
Correlated and exponential kidney and adrenal gland growth in volume and ratio
Firstly, as seen in Figure 5 below, the mean volume of the kidneys and adrenal glands are depicted and showing an exponential increase in volume with a correlation of r=0.9851172 (p=8.149e-06). The growth rate of the kidney and adrenal volume remained similar to one another up until week 19. After week 19, the kidneys acquired a volume up to 1.59ml (a 31.2-fold increase) and have grown relatively more in volume than the adrenal glands which reached 0.65ml (a 16.9-fold increase). The increase in volume differences between the two organs can equally be seen in Figure 6, depicting the total volume ratio between the kidneys and adrenal glands. Between 13 and 19 weeks of gestation, the ratio fluctuated between 1.4 and 2, with the kidneys having a higher volume compared to the adrenal glands. After week 19, it has risen to 2.3 or above. This increasing ratio, with the volume of the kidneys increasing with a higher rate compared to the adrenal glands, was linear.
Figure 4 - The kidneys (brown) and adrenal glands (green) from TOP9 (21+5 weeks of gestation) reconstructed with AMIRA in 3D coronal plane.
0 0.5 1 1.5 2 2.5 13 14 15 16 17 18 19 20 21 22 23 V o lu m e in m l
Gestational age (weeks)
The mean volume of kidneys and adrenal glands
Mean kidney volume Lorrez et al., (2020) Mean adrenal volume Lorrez et al., (2020) Expon. (Mean kidney volume Lorrez et al., (2020)) Expon. (Mean adrenal volume Lorrez et al., (2020))
0 0.5 1 1.5 2 2.5 3 3.5 4 13 14 15 16 17 18 19 20 21 22 23 R ati o
Gestational age (weeks)
Kidney : adrenal gland ratio based on total volume
Kidney : adrenal gland ratio volume Lorrez et al., (2020) Linear (Kidney : adrenal gland ratio volume Lorrez et al., (2020))
Figure 5 - The mean volume of the kidneys (blue) and adrenal glands (orange) depicted in ml over 10 weeks of gestational age. The results originate from the research of the author, Lorrez et al., (2020).
Figure 6 - The ratio of the total volumes of the kidneys and adrenal glands over the course of 10 weeks. The results were obtained from the research of the author, Lorrez et al., (2020).
Correlated and exponential kidney and adrenal gland growth in length
To further assess the growth of the kidneys and adrenal glands in volume, the lengths of the kidneys and adrenal glands have been measured. Figure 7 shows the mean length of both the left and the right kidneys. As visible, the left kidney was consistently longer than the right. They started at approximately 6.58mm and have grown up to between 19.16mm and 20.60mm. A 3-fold increase on average. The growth of the left and right kidney, with a correlation of r=0.9962505 (p=1.314e-07), correlated well with one another throughout the weeks. Figure 8 shows the mean length of the left and the right adrenal glands. Similar results could be seen for the adrenal glands. They started at approximately 5.35mm and 6.32mm and have grown up to 14.69mm and 15.61mm. An approximate 2.5-fold increase. The lines in the graph correlated well (r=0.9897567, p=2.666e-06) throughout the 10 weeks examined. However, the right adrenal gland was longer than the left adrenal gland. It started with a longer length and smoothened out towards the end.
0 5 10 15 20 25 13 14 15 16 17 18 19 20 21 22 23 Len gt h in m m
Gestational age (weeks)
The mean length of kidneys
Left kidney Lorrez et al., (2020) Right kidney Lorrez et al., (2020) Expon. (Left kidney Lorrez et al., (2020)) Expon. (Right kidney Lorrez et al., (2020))
Figure 7 - The mean lengths of the left (blue) and right (red) kidneys in mm over a span of 10 weeks of gestation. The results were obtained from the research of the author, Lorrez et al., (2020).
Correlated and exponential combined kidney and adrenal gland growth in lengths and ratio
To compare the changes of the kidneys and adrenal glands, the following two figures depict the growth, comparing the organs together. Figure 9 shows the mean length of the kidneys and adrenal glands. The lines in the graph followed an exponential trend and correlated well (r=0.9801988, p=1.912e-05) throughout the weeks, with the kidneys growing 3.02-fold and the adrenal glands 2.59-fold from their start values. These findings are also supported by Figure 10 which shows the ratio between the lengths. As seen in the graph, the points fluctuated from 1.03 to 1.41. Again, here the kidneys were longer in length. The graph corresponded with a linear growth. Slight increased ratios could be seen in weeks 15 and 21 of gestation.
0 2 4 6 8 10 12 14 16 18 13 14 15 16 17 18 19 20 21 22 23 Len gt h in m m
Gestational age (weeks)
The mean length of adrenal glands
Left adrenal gland Lorrez et al., (2020) Right adrenal gland Lorrez et al., (2020) Expon. (Left adrenal gland Lorrez et al., (2020)) Expon. (Right adrenal gland Lorrez et al., (2020))
Figure 8 - The mean lengths of the left (black) and right (yellow) adrenal glands over a span of 10 weeks. The results were obtained from the research of the author, Lorrez et al., (2020).
0 5 10 15 20 25 13 14 15 16 17 18 19 20 21 22 23 Le n gth in m m
Gestational age (weeks)
The mean length of kindeys and adrenal glands
Mean kidney Lorrez et al., (2020) Mean adrenal gland Lorrez et al., (2020) Expon. (Mean kidney Lorrez et al., (2020)) Expon. (Mean adrenal gland Lorrez et al., (2020))
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 13 14 15 16 17 18 19 20 21 22 23 R ati o in m m
Gestational age (weeks)
Kidney : adrenal gland length ratio based on mean
Kidney : adrenal gland ratio Lorrez et al., (2020) Linear (Kidney : adrenal gland ratio Lorrez et al., (2020))
Figure 9 - The mean length of the kidneys (blue) and the adrenal glands (orange) in mm over 10 gestational weeks. The results were acquired from the research of the author, Lorrez et al., (2020).
General T11 to L2 position of the kidneys and T9 to L1 position of the adrenal glands relative
to the vertebrae
The positions of the kidneys and adrenal glands can prove to be useful in identifying them on the prenatal ultrasounds. Figure 11 shows the position of the kidneys from cranial to caudal relative to the vertebra column. Most of the kidneys in the fetuses examined, the cranial border was located at the level of the eleventh thoracic vertebra (T11) and the caudal border at the level of the second lumbar vertebra (L2). The exceptions can be seen in weeks 14, 21, 22 and 23 of gestation. What can be seen is that a trend arises the older the fetuses are. The left kidneys have tended to grow in length along the vertebrae more than the right kidneys. Additionally, the right kidneys moved along downwards with the growth of the spine. Figure 12 show the position of the adrenal glands against the vertebrae from cranial to caudal. A trend is seen in the graph, as the adrenal glands moved along the spine downwards, with the left adrenal gland being longer and staying higher next to the spine compared to the right adrenal gland.
Figure 11 - The left (red) and right (blue) kidney positions against the the vertebrae from T11 to L5, plotted against the
Systematic review
With a thorough search in PubMed, 771 articles were identified and imported into Rayyan. Another 29 articles were found through other resources such as checking reference lists of previous systematic reviews and other relevant articles. With the help of Rayyan, 361 duplicates were removed, resulting in 439 articles to be screened based on the title and abstract. From this screening, 420 were eliminated and the remaining 19 were assessed for full-text eligibility. From the latter assessment, 9 were excluded and a total of 10 articles remained for the data-analysis. A PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analysis) flowchart, Figure 13, has been used to depict the results of the study selection (Moher et al., 2009). Of these 10 articles, two focused on volume and the remaining eight on length. A summary of the most important study characteristics of the included articles can be seen in table 2. No articles that were selected for the data-analysis were excluded based Figure 12 - The left (red) and right (blue) adrenal gland positions against the vertebrae from T9 to L3, plotted against the gestational ages of each single fetus used in the research of the author, Lorrez et al., (2020).
used for the study and if the results that were divided per age group. For the specimen age and inclusion criteria, one article was ‘unclear’. The visualisation technique was ‘unclear’ in two articles and the analysis was ‘unclear’ in four articles and not present in one article.
Table 2 - Characteristics of the 10 included articles for the systematic review. The study, study population, objective, parameter and techniques described.
Study Study population Objective Parameter Techniques
Diniz et al., 2019 Healthy fetuses between 12 to 23 gestational weeks (n = 84; 44
To evaluate the renal parenchymal area in human fetuses.
Volume Dissection Figure 13 - PRISMA chart for the extraction of relevant articles for the data-analysis, from identification to inclusion.
Kuno et al., 2006 Healthy fetuses from 20 w gestational eeks onwards. (n = 13)
To evaluate the growth of the fetal kidney in normal pregnancies using 3D ultrasound. Volume Ultrasound Ansari et al., 1997 Healthy fetuses between 16 to 40 gestational weeks. (n = 793)
Assess the different sizes of kidneys in Bangladesh. Length Ultrasound Cohen et al., 1991 Healthy fetuses between 18 to 41 gestational weeks. (n = 397) To measure normal length of fetal kidneys sonographically during pregnancies. Length Ultrasound Edevbie & Akhigbe. 2018 Healthy fetuses between 20 to 41 gestational weeks. (n = 400)
Measuring the fetal kidney sizes. Length Ultrasound Konje et al., 1997 Healthy fetuses between 22 to 38 gestational weeks. (n = 219) To determine whether there are differences in kidney size and shape in small and appropriate for gestational age fetuses at different gestations. Length Ultrasound Konje et al., 1996 Healthy fetuses between 22 to 38 gestational weeks. (n = 87)
To examine the changes in kidney morphometry during gestation in fetuses that were either appropriate or small for gestational age. Length Ultrasound Shin et al., 2007 Healthy fetuses between 16 to 41 gestational weeks. (n = 261) Constructing normograms of fetal renal length and parenchymal area derived from ultrasounds
Length Ultrasound Witzani et al., 2006 Healthy fetuses between 16 to 39 gestational weeks. (n = 218) To evaluate age dependent changes in fetal kidney
measurements with MRI
Length MRI Zalel et al., 2002 Healthy fetuses between 14 to 17 gestational weeks. (n = 275) To establish a nomogram for early fetal kidney development during early gestation.
Comparison of the results from the current study with previous studies
Correlated and exponential growth in volume from Lorrez et al., (2020) with previous
research
In Figure 15, the mean volume from this research has been combined with that of Diniz et al., (2019) and Kuno et al., (2006). Diniz et al., (2019) used the dissection method (square) and investigated 84 fetuses between 12 and 23 weeks of gestation. Kuno et al., (2006) used ultrasounds (rounds) and examined 13 fetuses between 20 and 24 weeks of gestation. In the graph, the data obtained from the current study corresponded with the data obtained from literature, but the volumes obtained are all relatively smaller. The lines in the graphs were exponential and correlated. A correlation of r=0.9206747 (p=0.001175) was present when comparing Diniz et al., (2019) and Lorrez et al., (2020) and another correlation could be found between Kuno et al., (2006) and Lorrez et al., (2020) at r=0.1586786 (p=0.8986).
Figure 14 - The risk of bias assessment from 10 articles according to Cochrane Risk of Bias checklist. The articles where filtered on ‘yes’ (green), ‘no’ (red) and ‘unclear’ (blue).
Correlated and exponential growth in length from Lorrez et al., (2020) with previous
research
And lastly to complete with the comparison of the volume measurements, the mean length of the kidneys current research combined with the data from the remaining articles, previously mentioned, depicted in Figure 16. The majority of the articles inquired about the mean length of fetuses between 16 and 24 weeks of gestation using ultrasounds (dots). The square represents MRI (Witzani et al., 2006) and the triangle, micro-CT (Lorrez et al., 2020). See Table 2 for more accurate details. In the graph, the data obtained from this study lies lower and are shorter, compared to the data from previous studies, but followed the general trend. The lines in the graph were all exponential
0 0.5 1 1.5 2 2.5 3 12 13 14 15 16 17 18 19 20 21 22 23 24 V o lu m e in m l
Gestational age (weeks)
The mean volume of kidneys from current and previous
studies
Diniz et al., (2019) Lorrez et al., (2020) Kuno et al., (2006) Expon. (Diniz et al., (2019)) Expon. (Lorrez et al., (2020)) Expon. (Kuno et al., (2006))
Figure 15 - The mean volume of the kidneys from the author, Lorrez et al., (2020) in red compared to the data from Diniz et al., (2019) in blue and the data from Kuno et al., (2006) in black. The data is plotted against the gestational age in weeks. The dots represent the ultrasound technique, the square dissection and the triangles CT scans.
with Konje et al., (1996) and Konje et al., (1997) due to the too small corresponding data points. The correlation between Lorrez et al., (2020) and Edevbie et al., (2018) was the lowest one.
Table 3 - The correlations between the current study and those compared with previous literature, focussing on the lengths of the kidneys.
Authors
Correlation value
Lorrez et al., (2020) and Zalel et al., (2002) r=0.9362636 (p=0.001903) Lorrez et al., (2020) and Ansari et al., (1997) r=0.9674358 (p=0.00702) Lorrez et al., (2020) and Shin et al., (2007) r=0.6412486 (p=0.2436) Lorrez et al., (2020) and Witzani et al., (2006) r=0.8681934 (p=0.05629) Lorrez et al., (2020) and Cohen et al., (1991) r=0.9239648 (p=0.07604) Lorrez et al., (2020) and Edevbie et al., (2018) r=0.1491172 (p=0.9047)
0 3 6 9 12 15 18 21 24 27 30 33 13 14 15 16 17 18 19 20 21 22 23 24
Le
n
gt
h
of kid
n
ey
s
in
mm
Gestational age (weeks)
The mean length of kidneys from current and
previous studies
Lorrez et al., (2020) Zalel et al., (2002) Ansari et al., (1997) Shin et al., (2007) Witzani et al., (2006) Cohen et al., (1991) Edevbie et al., (2018) Konje et al., (1997) Konje et al., (1996)
Expon. (Lorrez et al., (2020)) Expon. (Zalel et al., (2002)) Expon. (Ansari et al., (1997)) Expon. (Shin et al., (2007)) Expon. (Witzani et al., (2006)) Expon. (Cohen et al., (1991)) Expon. (Edevbie et al., (2018)) Expon. (Konje et al., (1997)) Expon. (Konje et al., (1996))
Figure 16 - The mean lengths of the kidneys from the author Lorrez et al., (2020) in red, Zalel et al., (2002) in purple, Ansari et al., (1997) in black, Shin et al., (2007) in yellow, Witzani et al., (2006) in dark grey, Cohen et al., (1991) in green, Edevbie et al., (2018) in light blue, Konje et al., (1997) in dark blue and Konje et al., (1996) in light red. The results were plotted against the gestational age in
Discussion
The aim of this study was to expand the comprehension of the growth of the kidneys and adrenal glands between 10 and 24 weeks of gestation. This was possible with the help of AMIRA, a 3D programme, which allowed the labelling and measuring of the following parameters; volume, length and position.
As visualised in Figures 15 and 16, the data from the empirical research correlates well with the data from literature. The sample size regarding each gestational age is small and could therefore give partially unreliable results. In all analyses (Figures 5 through 16), at 21 weeks gestation, a peak can be seen. This peak could be caused by the Lugol’s solution the outlying fetus has been prepared in, as Lugol’s solutions causes concentration dependent tissue shrinkage (Heimel et al., 2019). The outlying fetus may have been immersed less long in this solution, causing additional unequal amounts of shrinkage. The gestational ages of the fetuses have been inspected by the author to rule out wrong ageing as the age of the fetus is obtained from hospital records provided at the time of donation. However, different hospitals may use different age-estimation methods which may cause discrepancies between included specimens. It was concluded that the outlying fetus had a discrepancy of only two days. The remaining foetuses had discrepancies ranging from one to 12 days. Another general remark that can be made regarding the volumes of the renal-adrenal system measurements is the acquirement of the mean. This study has obtained a total volume and divided this by two to acquire a mean. Previous researches have done it differently, using different methods and imaging techniques. However, overall, the data from this study corresponds well with the data from the previous research with regard to the general trends and shapes of the growth curves observed.
The volumetric measurements from this study, from the kidneys and adrenal glands indicate that these structures grow exponentially and correlate well with one another. The results when comparing the volumetric kidney data from literature also corresponds well with the data obtained from the author. Despite this correspondence, the comparison with other literature is limited, as only 2 other articles had been found. Bigger data sets would allow for a more thorough and reliable conclusion. Another observation made, is the author’s results lying lower than the results from previous research. A reason for this could be the Lugol’s solution (Heimel et al., 2019). The ratio of the volumetric data grows linearly, indicating consistent and communicated growth between the two organs and their position towards one another.
For the kidney and adrenal gland mean lengths, can be said that both the right and left organs grow equally and accordant. This is confirmed by the correlation values. A slight increase at week 14
can be seen in as the left kidney is bigger than the right kidney due to the position of the liver, but the right adrenal glands is larger than the left adrenal gland. As mentioned before in earlier research by Folligan et al., (2005), the left adrenal was bigger than right adrenal gland. The cause of this could be the period in which this is measured, as Folligan et al., (2005) measured until 28 weeks of gestation and the foetuses in this study allowed only up to 23+3 weeks. The combined kidney and adrenal gland length and the ratio based on the mean only but support the notion that the organs grow in accordance to one another. The mean lengths of kidneys from this study correspond well and correlate to a certain extent with the data obtained from previous research. The data perceived from AMIRA is smaller and lower than other research. This can be appointed to not only the different visualisation methods used in obtaining the length of the kidneys but also the measuring techniques, as they all differ amongst literature, and the Lugol’s solution (Heimel et al., 2019). The results from this study are the furthest apart with the data from Edevbie et al., (2018). Reasons for this could be the technique. Another remark that could be made regarding the discrepancies between the volume and length compared to previous literature. The amount of studies are more extensive in length than volume. No possible explanation could be found for this yet, but the number of articles for volume should be increased before any further presumptions are made.
Furthermore, the position of the kidneys against the vertebrae changes minimally in the 10 weeks of gestation examined. What can be seen particularly is that the left kidneys grow longer and occupies longer lengths the older the fetus. The right kidney does not seem to grow much but moves caudally. A possible reason for the downwards movement is the liver that pushes the right kidney for its own growth. The kidneys in this stage have reached their final position as seen in adulthood. As for the position of the adrenal glands relative to the vertebrae, a slightly different situation can be acknowledged. The more the fetuses age, the more they move caudally along the spine. This caudal movement can be relied back the growth of the liver, which pushes both the right adrenal gland and kidney downwards. The adrenal glands too are than in their final position.
As mentioned from previous research and stated above, the perceived lengths of adrenal glands from Folligan et al., (2005) of whom the differences have been discussed above. Knowing the growth pattern of the renal-adrenal system in terms of length and volume will aid future research in acknowledging kidney anomalies such as CAKUT (Capone et al., 2017) and congenital adrenal agenesis (D’Arcy et al., 2014). This could also increase the detection of the number of infants born with the most common congenital kidney diseases (Genetics Home Reference, 2020).
The models created in AMIRA are valid and reliable, as they are created and examined by experts in the field, despite the small sample size. To improve the accurateness, a solution should be found to prevent the shrinkage caused by Lugol’s solution. Afterwards, an increase in fetuses per
the gestational ages have been acquired for this research, therefore recommendations for future research are the completion of the 10 to 24 gestational weeks’ timeline with more fetuses and an expansion into the late second trimester and early third trimester. The reconstructed models will later be implemented into the 3D digital atlas from Bernadette de Bakker (2016) to not only diagnose anomalies earlier during routine ultrasounds, but also expand the knowledge of the renal-adrenal system.
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Appendix
A1. Final search string
("kidney*"[MeSH] OR kidney*[tiab] OR “renal”[MeSH] OR renal*[tiab] OR "suprarenal glands "[MeSH] OR suprarenal gland*[tiab] OR "adrenal gland"[MeSH] OR adrenal*[tiab])
AND
("fetus"[MeSH] OR fetus*[tiab] OR "foetus"[MeSH] OR foetus*[tiab] OR fetal*[tiab] OR foetal*[tiab] OR "fetal period"[MeSH]] OR pregnancy, first trimester[MeSH] or first trimester[tiab] OR pregnancy, second trimester[MeSH] OR second trimester[tiab])
AND
("anatomy"[MeSH] OR anatom*[tiab] OR "morphogenesis"[MeSH] OR morphogenesis*[tiab] OR "fetal development"[MeSH] OR fetal development*[tiab] OR "ontogeny"[MeSH] OR ontogeny*[tiab] OR "morphology"[MeSH] OR morpholog*[tiab] OR "growth and development"[MeSH] OR
growth*[tiab] OR development*[tiab]) AND
("humans"[MeSH] OR humans*[tiab]) AND
(“MRI”[MeSH] OR MRI*[tiab] OR “CT”[MeSH] OR CT*[tiab] OR “ultrasound”[MeSH] OR
ultrasound*[tiab] OR “dissection”[MeSH] OR dissection*[tiab] OR histology[MeSH] OR histol*[tiab])
A2. Data extraction & quality of the papers template from Higgins et al., (2011)
Data extraction Study ID Aim of study Gestational age Number of specimens Imaging technique
Quality papers
Methods – specimen age
Fully described
☐ Yes
☐ No
☐ Unclear
Methods – number of specimens
Fully described
☐ Yes
☐ No
☐ Unclear
Methods – inclusion criteria
Fully described
☐ Yes, healthy
☐ Yes, abnormality
☐ No
☐ Unclear
Methods – visualisation technique
Fully described
☐ Yes
☐ No
☐ Unclear
Methods – analysis
Fully described
☐ Yes
☐ No
☐ Unclear
Results – separate per age group
Fully described
☐ Yes
☐ No
☐ Unclear
Quality papers
Data extraction Study ID Diniz, A. L. L. (2019)Aim of study To evaluate the renal parenchymal area in human
fetuses.
Gestational age Between 12 and 23 weeks post conception.
Number of specimens 84 (44 male and 40 female)
Imaging technique Dissection
Region visualized The kidneys renal length, width of the superior pole, width of the inferior pole and renal thickness.
Volume/weight /
Notes Study of the renal parenchymal volume during the
human fetal period.
Methods – specimen age
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – number of specimens
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – inclusion criteria
Fully described
☒ Yes, healthy
☐ Yes, abnormality
☐ No
☐ Unclear
Methods – visualisation technique
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – analysis
Fully described
☒ Yes
☐ No
☐ Unclear
Results – separate per age group
Fully described
☒ Yes
☐ No
☐ Unclear
No other remarks.
Data extraction Study ID Cohen, H.L. (1991)Aim of study To measure normal length of fetal kidneys
sonographically during pregnancies.
Gestational age Between 18 – 41 weeks
Number of specimens 397 fetuses and 498 kidneys
Imaging technique Sonographs
Region visualized Kidneys
Volume/weight /
Notes Normal length of fetal kidneys: sonographic
study in 297 obstetric patients. Doi: 10.2214/ajr.157.3.1872242
Quality papers
Methods – number of specimens
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – inclusion criteria
Fully described
☒ Yes, healthy
☐ Yes, abnormality
☐ No
☐ Unclear
Methods – visualisation technique
Fully described
☐ Yes
☐ No
☒ Unclear
Methods – analysis
Fully described
☒ Yes
☐ No
☐ Unclear
Results – separate per age group
Fully described
☒ Yes
☐ No
☐ Unclear
The results of fetal lenghts are longer than
mentioned in other studies.
Data extraction
Study ID Edevbie, J. P. (2018)
Aim of study Measuring the fetal kidney.
Gestational age Between 20 to 41 weeks
Number of specimens 400
Imaging technique US
Region visualized Kidneys, both left and right
Volume/weight /
Notes Ultrasound measurement of fetal kidney length
in normal pregnancy and correlation with gestational age.
Doi: 10.4103/njcp.njcp_373_15
Quality papers
Methods – specimen age
Fully described
☐ Yes
☐ No
☒ Unclear
Methods – number of specimens
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – inclusion criteria
Fully described
☒ Yes, healthy
☐ Yes, abnormality
☐ No
☐ Unclear
Methods – visualisation technique
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – analysis
Fully described
☒ Yes
☐ No
☐ Unclear
Results – separate per age group
Fully described
☒ Yes
☐ No
☐ Unclear
The information is not very clear in the
article. It is sometimes very hard to find.
Data extraction
Study ID Witzani, L. (2006)
Aim of study To evaluate age dependent changes in fetal
kidney measurements with MRI
Gestational age Between 16-39 weeks
Number of specimens 218 for kidney length, 223 for signal intensities and 107 for apparent diffusion coefficient
Imaging technique MRI
Region visualized Abdominal area kidneys
Volume/weight /
Notes Normal renal development investigated with
fetal MRI
Doi: 10.1016/j.ejrad.2005.11.027
Quality papers
Methods – specimen age
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – number of specimens
Fully described
☒ Yes
☐ No
☒ Yes, healthy
☐ Yes, abnormality
☐ No
☐ Unclear
Methods – visualisation technique
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – analysis
Fully described
☒ Yes
☐ No
☐ Unclear
Results – separate per age group
Fully described
☒ Yes
☐ No
☐ Unclear
A strange way is haunted for sorting the
fetuses per experiment.
Data extraction
Study ID Ansari, S.M. (1997)
Aim of study Assess the different sizes of kidneys in
Bangladesh.
Gestational age Between 16 – 40 weeks
Number of specimens 793 fetuses
Imaging technique Ultrasonograms
Region visualized Kidneys
Volume/weight /
Notes Ultrasonographic study of 793 foetuses:
measurement of normal foetal kidney lengths in Bangladesh.
Doi: 10.1111/j.1440-1673.1997.tb00457.x
Quality papers
Methods – specimen age
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – number of specimens
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – inclusion criteria
Fully described
☐ Yes, healthy
☐ Yes, abnormality
☐ No
☒ Unclear
Methods – visualisation technique
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – analysis
Fully described
☐ Yes
☒ No
☐ Unclear
Results – separate per age group
Fully described
☒ Yes
☐ No
☐ Unclear
They only discribe the inclusion criteria as
‘normal’ pregnancies.
Data extraction
Study ID Kuno, A. (2006)
Aim of study To evaluate the growth of the fetal kidney in
normal pregnancies using 3D ultrasound.
Gestational age From 20 weeks onwards
Number of specimens 13
Imaging technique US
Region visualized Kidneys
Volume/weight /
Notes Three-dimensional sonographic measurement
of fetal renal volume.
Doi: 10.1007/s10396-005-0067-6
Quality papers
Methods – specimen age
Fully described
☒ Yes
☐ No
☒ Unclear
Methods – number of specimens
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – inclusion criteria
Fully described
☒ Yes, healthy
☐ Yes, abnormality
☐ No
☒ Yes
☐ No
☐ Unclear
Methods – analysis
Fully described
☐ Yes
☐ No
☒ Unclear
Results – separate per age group
Fully described
☒ Yes
☐ No
☐ Unclear
The number of examiners was only one in
two investigations.
Data extraction
Study ID Konje, J.C. (1996)
Aim of study To examine the changes in kidney morphometry
during gestation in fetuses that were either appropriate or small for gestational age.
Gestational age Between 22-38 weeks
Number of specimens 87
Imaging technique US
Region visualized kidneys
Volume/weight /
Notes Human fetal kidney morphometry during
gestation and the relationship between weight, kidney morphometry and plasma active renin concentration at birth
Doi: 10.1042/cs0910169
Quality papers
Methods – specimen age
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – number of specimens
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – inclusion criteria
Fully described
☒ Yes, healthy
☐ Yes, abnormality
☐ No
☐ Unclear
☐ No
☐ Unclear
Methods – analysis
Fully described
☐ Yes
☐ No
☒ Unclear
Results – separate per age group
Fully described
☒ Yes
☐ No
☐ Unclear
The sample size is quite small and they
compare them to cadavers which are older
and irrelevant in our study here.
Data extraction
Study ID Konje. J.C. (1997)
Aim of study To determine whether there are differences in
kidney size and shape in small and appropriate for gestational age fetuses at different
gestations.
Gestational age Between 22 – 38 weeks
Number of specimens 219
Imaging technique US
Region visualized Kidneys
Volume/weight /
Notes A cross sectional study of changes in fetal renal
size with gestation in appropriate and small-for-gestational age fetuses.
Quality papers
Methods – specimen age
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – number of specimens
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – inclusion criteria
Fully described
☒ Yes, healthy
☐ Yes, abnormality
☐ No
☒ Unclear
Methods – analysis
Fully described
☒ Yes
☐ No
☐ Unclear
Results – separate per age group
Fully described
☒ Yes
☐ No
☐ Unclear
The method with which the kidneys were
measured is unclear.
Data extraction
Study ID Shin, JS. (2007)
Aim of study Constructing normograms of fetal renal length
and parenchymal area derived from ultrasounds
Gestational age Between 16-41 weeks
Number of specimens 261
Imaging technique US
Region visualized Kidneys
Volume/weight /
Notes Normogram of fetal renal growth expressed in
length and parenchymal area derived from ultrasound images
Doi: 10.1016/j.juro.2007.07.044
Quality papers
Methods – specimen age
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – number of specimens
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – inclusion criteria
Fully described
☒ Yes, healthy
☐ Yes, abnormality
☐ No
☐ Unclear
Methods – visualisation technique
Fully described
☐ Yes
☐ No
☒ Unclear
☐ Yes
☐ No
☒ Unclear
Results – separate per age group
Fully described
☒ Yes
☐ No
☐ Unclear
Data extraction
Study ID Zalel, Y. (2002)
Aim of study To establish a nomogram for early fetal kidney
development during early gestation.
Gestational age Between 14 – 17 weeks
Number of specimens 275 fetuses
Imaging technique US
Region visualized Kidneys
Volume/weight /
Notes The early development of the fetal kidney – an
in utero sonographic evaluation between 13- and 22-weeks’ gestation.
Doi: 10.1002/pd.436
Quality papers
Methods – specimen age
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – number of specimens
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – inclusion criteria
Fully described
☒ Yes, healthy
☐ Yes, abnormality
☐ No
☐ Unclear
Methods – visualisation technique
Fully described
☒ Yes
☐ No
☐ Unclear
Methods – analysis
Fully described
Results – separate per age group
Fully described
☒ Yes
☐ No
☐ Unclear
Some of the groups for the gestational age
were so small that some of the values might
be unreliable.
Fig u re 17 T h e sp eci fi ed vo lu m es w ith o u t th e o u tl yi n g fe tu s TO P 9 . S p eci fi ed m ea n in g th a t a ll th e fe tu se s w ith th e sa m e g est a ti o n a l a g e h a ve b ee n co m b in ed . T h e to ta l k id n ey vo lu m e, th e m ea n k id n ey vo lu m e, th e to ta l a d re n a l g la n d v o lu m e, th e m ea n a d re n a l g la n d vo lu m e a n d th e k id n ey: a d re n a l g la nd ra ti o n b a se d o n th e to ta l vo lu m e a re p o rtr a ye d h er e. Fig ure 18 - T he s pec ified vo lum es w ith t he ou tly ing f et us a re depi ct ed he re . S pec ified m eani ng tha t a ll t he f e tus es w ith t he s am e g es ta tiona l a ge ha ve been com bi ned. T he t o ta l k idney v o lume, the m ea n k idn ey v o lume, the t o ta l a drena l gl and vo lume, the m ea n a drena l g la nd vo lume and the kidney: adre na l g la nd ra tio us ing t he t o ta l v ol ume a re depi ct ed her e. Fig u re 19 - T h e g en er a l vo lu m e d a ta fo r e a ch fe tu s a cq u ire d in th e r ese a rch o f th e a u th o r, Lo rre z e t a l., (2 0 20 ). Th e to ta l k id n ey vo lu m e, m ea n k id n ey vo lu m e, to ta l a d re na l g la nd vo lu m e, m ea n a d re n a l g la n d v o lu m e a n d th e k id n ey: a d re n a l g la n d ra ti o u si n g th e to ta l vo lu m e a re d ep icte d h er e.
Fig u re 20 - T h e sp eci fi ed le n g th d a ta fo r e a ch fe tu s w ith o u t th e o u tl yi n g fe tu s T O P 9 , a cq u ire d in th e r ese a rch o f th e a u th o r, Lo rre z e t a l., (2 0 2 0 ). Sp eci fi ed m ea n in g th a t th e d a ta fr o m th e fe tu se s w ith th e sa m e g est a ti o n a l a g e a re p u t to g eth er . T h e l eft a n d rig h t a d re n a l g la n d le n g th s, th e m ea n a d re n a l g la n d le n g th s a n d th e k id n ey: a d re n a l g la n d ra ti o u si n g th e m ea n le n g th s a re d ep icte d h er e. Fig ure 22 - T he s pec ified l eng th da ta f or ea ch f e tus a cqui re d i n the re search of t he aut hor, L orrez et a l., ( 2 0 2 0 ). S pec ified me ani ng t ha t t he da ta f rom the f et us es w ith t he sa me g es ta tiona l a ge are put toge ther . T he l eft a nd ri gh t k idne y l eng ths , t he me an k idney k idney leng ths , t he l ef t a nd ri ght a d re na l g la nd l eng ths , t he me an a dre na l g la nd leng ths a nd t he k idney: adre na l g la nd ra tio us ing t he me an leng ths a re depi ct ed he re . Fig ure 21 - T he g ene ra l l eng th da ta f or ea ch f e tus a cqui re d i n t he re search of t he aut hor, L orrez et a l., ( 2 0 2 0 ). T he l eft a nd ri ght k idney l eng ths , t he me an kidney l eng ths , t he l ef t a nd ri ght a dre na l g la nd l eng ths , t he m ean a dre na l g la nd l eng ths a nd t he kidney: adre na l g la nd ra tio u sing t he me an l eng ths a re depi ct ed h ere.
A4. Graphs without the outlying fetus TOP9
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 13 14 15 16 17 18 19 20 21 22 23 V o lu m e in m lGestational age (weeks)
The mean volume of the kidneys and adrenal glands
without TOP9
Mean kidney volume Lorrez et al., (2020) Mean adrenal volume Lorrez et al., (2020) Expon. (Mean kidney volume Lorrez et al., (2020)) Expon. (Mean adrenal volume Lorrez et al., (2020))
0 0.5 1 1.5 2 2.5 3 3.5 4 13 14 15 16 17 18 19 20 21 22 23 R ati o in m l
Gestational age (weeks
Kidney : adrenal gland ratio based on total volume
without TOP9
Kidney : adrenal gland ratio volume Lorrez et al., (2020) Linear (Kidney : adrenal gland ratio volume Lorrez et al., (2020))
Figure 23 - The mean volume of the kidneys (black) and adrenal glands (green) depicted in ml over 10 weeks of gestational age without TOP9. The results originate from the research of the author, Lorrez et al., (2020).
