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Abdominal Radiology (2022) 47:288–296 https://doi.org/10.1007/s00261-021-03296-1

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KIDNEYS, URETERS, BLADDER, RETROPERITONEUM

Evaluation of renal fibrosis in various causes of glomerulonephritis by MR elastography: a clinicopathologic comparative analysis

Alper Tuna Güven1  · Ilkay S. Idilman2 · Cebrayil Cebrayilov3 · Ceren Önal3 · Müge Üzerk Kibar3 · Arzu Sağlam4 · Tolga Yıldırım3 · Rahmi Yılmaz3 · Bülent Altun3 · Yunus Erdem3 · Muşturay Karçaaltıncaba2 · Mustafa Arıcı3

Received: 8 July 2021 / Revised: 22 September 2021 / Accepted: 27 September 2021 / Published online: 11 October 2021 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

Abstract Background Renal parenchymal fibrosis is the most important determinant of kidney disease progression and it is determined via biopsy. The aim of this study is to evaluate the renal stiffness noninvasively by magnetic resonance elastography (MRE) and to compare it with clinicopathologic parameters in glomerulonephritis and AA amyloidosis patients. Methods Thirty-four patients with glomerular filtration rate (GFR) over 20 ml/min/1.73m2 had non-contrast MRE prospec- tively. Kidney stiffness values were obtained from whole kidney, cortex, and medulla. Values were correlated with GFR, albuminuria, proteinuria, and degree of fibrosis that are assessed via renal biopsy. Patients were grouped clinicopathologi- cally to assess the relation between stiffness and chronicity. Results Mean whole kidney, cortex, and medulla stiffnesses were 3.78 (± 1.26), 3.63 (± 1.25), and 4.77 (± 2.03) kPa, respectively. Mean global glomerulosclerosis was 22% (± 18%) and median segmental glomerulosclerosis was 4% (min– max: 0%–100%). Extent of tubulointerstitial fibrosis was less than 25% in 26 of the patients (76.5%), 25%–50% in 6 of the patients (17.6%), and higher than 50% in 2 of the patients (5.9%). Fourteen patients were defined to have chronic renal parenchymal injury. MRE-derived stiffness values correlated negatively with parameters of fibrosis. Lower stiffness values were observed in patients with chronic renal injury compared to those without (P < 0.05 for whole kidney and medulla MRE-derived stiffness). Conclusion MRE-derived stiffness values were lower in patients with chronic injury. Stiffness decreases as glomeruloscle- rosis and tubulointerstitial fibrosis progresses in patients with primary glomerulonephritis and AA amyloidosis. With future studies, there may be a role for MRE to assess renal function in concert with conventional markers.

Keywords Magnetic resonance imaging · Glomerulonephritis · Amyloidosis · Fibrosis · Kidney biopsy

Introduction

Kidney fibrosis is the manifestation of chronic paren- chymal injury to most glomerular and tubulointerstitial insults [1, 2]. As fibrosis is one of the major determinants

of outcome, it is crucial to determine its extent and sever- ity for diagnostic and therapeutic purposes [3, 4]. Firstly, GFR may not decrease despite presence of renal fibro- sis, sometimes not until the point where fibrotic damage is extensive, due to the kidney’s inherent compensatory capacity. Secondly, decreases in GFR may not only be related with the chronic damage/parenchymal fibrosis [5]. Hence estimating GFR via serum markers provides only rough and approximate estimations of kidney fibrosis and may in fact even be misguiding. The most accurate way of assessing kidney fibrosis is to obtain a kidney biopsy [6]. Biopsy is not only an invasive procedure with com- plications and contraindications, but also prone to sam- pling errors by sampling < 1% of the kidney parenchyma. Taking into account the heterogeneous and patchy dis- tribution of fibrosis within kidneys, the value of kidney

* Alper Tuna Güven [email protected]

1 Department of Internal Medicine, Faculty of Medicine, Hacettepe University, Ankara, Turkey

2 Department of Radiology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

3 Department of Nephrology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

4 Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

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biopsy may be further impaired [6–9]. It is also unrealis- tic to obtain serial biopsies over time to measure degree of fibrosis. The necessity to assess fibrosis noninvasively and accurately led to studies involving various imaging techniques, including ultrasound and magnetic resonance imaging (MRI) [10]. While multiple MRI techniques have been studied in order to assess fibrosis [11–21], magnetic resonance elastography (MRE) seems to hold promise [5, 22–27]. MRE combines MRI with the assessment of acoustic waves for the quantitative determination of vis- coelastic properties of tissues based on their response to external mechanical vibration and was originally devel- oped to assess liver fibrosis [28]. Studies in kidneys dem- onstrated that MRE correlates with the level of fibrosis in renal allografts and diabetic kidneys. These studies have shown that while kidney stiffness increases with increasing levels of fibrosis in cirrhotic liver and renal allografts [24, 25, 27], kidney stiffness decreases in diabetic nephropathy [5]. To date, no study has evaluated the relation of kid- ney fibrosis and stiffness in various primary glomerular diseases and AA amyloidosis patients. The aim of this study is to assess kidney parenchymal fibrosis in glomeru- lonephritis and AA amyloidosis patients using 2D MRE- derived stiffness as a surrogate marker and compare MRE findings with clinicopathological correlates of glomerular diseases.

Materials and methods

Patients

Patients with primary glomerular diseases with GFR > 20 ml/min/1.73m2 who had undergone renal biopsy were recruited. Exclusion criteria were acute kidney injury, pregnancy, renal transplantation, prior corticos- teroids or immunosuppressive use, secondary glomeru- lar diseases, presence of hydronephrosis and renal vein thrombosis on conventional MRI sequences and contrain- dications to MRI, and declining the informed consent. Patients underwent MRE prior to kidney biopsy. MRE acquisition and kidney biopsy were both performed on the same (left) kidney. The study was approved by Hacettepe University Non-Invasive Clinical Studies Ethical Commit- tee (GO 18/1147). Written informed consent was obtained from each patient. No adverse event occurred related to the study. Clinical data regarding age, gender, serum creatinine (mg/dl), GFR (using CKD-EPI equation, ml/ min/1.73m2), serum albumin (gr/dl), serum protein (gr/dl), urine protein to creatinine ratio (mg/gr creatinine), urine albumin to creatinine ratio (mg/gr creatinine) 24-h albu- min, and protein in urine (mg/24 h) before biopsy were

collected from each patient’s electronic health records at the study entry.

Kidney biopsy and histopathological examination

All patients underwent ultrasound-guided percutaneous kidney biopsy after their MRE acquisitions. All biopsies were reported by a blinded nephropathologist with substan- tial expertise who was unaware of the MRE results. Jones’ methenamine silver (JMS), Masson’s trichrome stain, peri- odic acid methenamine silver (PAMS), periodic acid–Schiff (PAS), and Congo red stains were performed on biopsy specimens as part of the routine kidney biopsy workup. Immunofluorescence stains for IgA, IgG, IgM, C3, C4, C1q, kappa, and lambda were performed as part of the routine kidney biopsy workup as well. Histopathological parameters assessed as markers of chronic renal injury (renal fibrosis) were extent of global glomerulosclerosis, segmental glo- merulosclerosis, and tubulointerstitial fibrosis. Global and segmental glomerulosclerosis were reported in percentages and tubulointerstitial fibrosis was reported categorically as comprising < 25%, 25%–50%, and > 50 percent of the corti- cal renal parenchyma.

Determination of the chronicity

The patients were grouped according to evidence of chronic renal injury. This grouping was based on both clinical and pathologic parameters, taking into consideration of the biopsy findings, serum parameters and their course over time, and response to treatment. More than 50% of global sclerosis and > 50% cortical tubulointerstitial scarring were considered as histopathologic parameters of chronic renal injury. Persistently elevated serum creatinine, development of unremitting proteinuria, and persistently low GFR were accepted as the clinical parameters of chronicity. If clinical follow-up (i.e., trends in serum creatinine, level of protein- uria) suggested chronic renal injury despite less extensive global glomerular sclerosis and tubular atrophy/interstitial fibrosis, the patient was included in the group with chronic renal parenchymal injury.

MR elastography and analysis

MR imaging was performed with a 1.5-T MR system (Mag- netom Aera, Siemens Healthcare, Erlangen, Germany). A 30-channel phased array body coil was used for this acqui- sition. The subjects were examined in supine position. The placement of passive driver is shown in Fig. 1a and three- plane localization imaging gradient echo sequence was per- formed at the beginning of the examination. The parameters of MRE were as follows: TR/TE, 50/21.41 ms; flip angle 25°; section thickness 50 mm; field-of-view FOV 350 × 350

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mm2. Using a workstation, regions of interest (ROIs) were drawn as geographic areas guided by the magnitude image to include kidney parenchyma, medulla, and cortex of the kidney by excluding areas close to the kidney margins and collecting system.

Statistical analysis

Shapiro–Wilk test of normality was used to determine dis- tribution of variables. Normally distributed variables were reported as mean (± standard deviation) and non-normally distributed variables were reported as median (mini- mum–maximum). Spearman’s correlation analysis was used to assess correlation between MRE-derived stiffness values, clinical data, and histopathological data. Mann–Whitney U test was used as non-parametric test to assess distribution of independent samples. IBM SPSS statistics version 22.0 was used for statistical analysis. For all tests, a two-tailed P

value of less than 0.05 was considered statistically signifi- cant (Figs. 2, 3).

Results

Clinical data

A total of 39 patients were enrolled in the study between December 2018 and January 2020. Five patients were excluded as their biopsy results did not meet inclusion cri- teria for the study. Four patients did not have urine albumin to creatinine ratio data. Only 16 patients had 24-h protein in urine data. Median serum creatinine levels were 0.95 mg/ dl (range, 0.2–3.7), median serum albumin and protein lev- els were 3.18 gr/dl (range, 1.3–4.4) and 6.04 gr/dl (range, 3.9–7.6), respectively, median urine albumin to creatinine and median protein to creatinine ratios were 2518 mg/gr

Fig. 1 MRE set-up and optimal passive driver placement are seen on both illustration a and localizer image (b)

Fig. 2 MR stiffness measure- ment for kidney. A freehand ROI was drawn on the magni- tude image a and then copied to the stiffness map (b)

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creatinine (range, 78–9016) and 3656 mg/gr creatinine (range, 475–18,193), respectively. Fourteen patients were assessed as displaying evidence of chronic renal parenchy- mal injury (CRPI), whereas 20 did not display evidence of CRPI. Patients with evidence of CRPI had lower median cre- atinine, higher albumin and protein levels, and lower urine albumin to creatinine and urine protein to creatinine ratios than those lacking evidence of CRPI (all P < 0.05). Patient’s clinical data are shown in detail in Table 1.

Histopathological characteristics

Of the 34 patients, 12 had membranous nephropathy, 10 had focal segmental glomerulosclerosis, 5 had AA

amyloidosis, 4 had IgA nephropathy, and the remaining 3 patients had membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis plus IgA nephropa- thy, and focal segmental glomerulosclerosis plus Alport syndrome. Ratio of mean global glomerulosclerosis was 22% (± 18%) and median segmental sclerosis score was 4% (range, 0%–100%). Extent of tubulointerstitial fibro- sis was less than 25% in 26 of the patients (76.5%), 25 to 50% in 6 of the patients (17.6%), and higher than 50% in 2 of the patients (5.9%). Patients with evidence of CRPI had higher global and segmental glomerulosclerosis per- centages compared to those lacking evidence of CRPI (all P < 0.05). Patients’ histopathological characteristics are shown in detail in Table 2.

Fig. 3 MR stiffness measurements for renal cortex and medulla. Freehand ROI was used for delineation of medulla a and cortex d on T1W image and copied to the magnitude image b and e and stiffness map (c and f)

Table 1 Clinical characteristics of all patients and their subgroups as CRPI and Non-CRPI patients

BUN Blood urea nitrogen, CRPI Chronic renal parenchymal injury

Parameters Results mean (± SD) or median (Min–Max) Distribution

All Patients CRPI Non-CRPI P

Serum albumin (gr/dl) 3.1 (1.3–4.4) 3.77 (2.7–4.4) 2.75 (1.3–4.1) P < 0.01 Serum protein (gr/dl) 6.0 (3.9–7.6) 6.80 (5.4–7.6) 5.51 (3.9–7.4) P < 0.01 BUN (mg/dl) 17 (6–95) 25 (17–59) 12 (6–95) P < 0.01 Serum creatinine (mg/dl) 0.9 (0.2–3.7) 1.5 (1.0–3.7) 0.9 (0.2–2.5) P < 0.01 Urine albumin to creatinine (mg/gr creatinine) 2518 (78–9016) 1816 (78–4050) 3254 (419–9016) P < 0.05 Urine protein to creatinine (mg/gr creatinine) 3656 (475–18,193) 2670 (475–5406) 4300 (984–18,193) P < 0.05 24-h urine albumin (mg/24 h) 2628 (422–3354) 2452 2772 (422–3354) P > 0.05 24-h urine protein (mg/24 h) 3768 (1122–20,284) 2580 (1874–7539) 4224 (1122–20,284) P > 0.05

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MR elastography data

Regarding all patients, mean whole kidney stiffness was 3.78 kPa (± 1.26), cortex stiffness was 3.63 kPa (± 1.25), and medulla stiffness was 4.77 kPa (± 2.04). Whole kidney, cortex, and medulla stiffness values were lower across the group of patients with evidence of CRPI compared to those lacking evidence of CRPI (all P < 0.05, except for the cortex stiffness, P = 0.112) (Table 3).

Relationship between MRE‑derived stiffness and clinical parameters

Whole kidney, cortex, and medulla MRE-derived stiffness values correlated positively with urine albumin to creati- nine, urine protein to creatinine, and 24-h protein in urine. Whole kidney, cortex, and medulla MRE-derived stiffness values correlated negatively with serum albumin and serum protein levels. Whole kidney and medulla MRE-derived stiffness also correlated negatively with creatinine levels. Regarding the group of patients with evidence of CRPI, no correlation was observed between serum albumin, pro- tein; urine albumin, protein levels, and stiffness values. The group of patients lacking evidence of CRPI showed no cor- relation between BUN, creatinine, and stiffness, but whole

kidney and cortex stiffness values correlated negatively with serum albumin (r = − 0.483 and -0.540, P < 0.05) and protein (r = − 0.562 and − 0.571, P < 0.05). Correlation data regard- ing MRE-derived stiffness and clinical parameters are shown in detail in Table 4.

Relationship between MRE‑derived stiffness and histopathological parameters

Whole kidney and medulla MRE-derived stiffness corre- lated negatively with extent of global glomerulosclerosis, segmental glomerulosclerosis, and tubulointerstitial fibro- sis. In contrast to these correlations, cortex MRE-derived stiffness did not correlate with global glomerulosclerosis

Table 2 Histopathological characteristics of all patients and their subgroups as CRPI and Non-CRPI patients

CRPI Chronic renal parenchymal injury

Parameters Results mean (± SD) or median (Min–Max)

All Patients CRPI Non-CRPI

Global glomerulosclerosis 22% (± 18%) 39% (± 12%) 6% (0–32%) Segmental glomerulosclerosis 4% (0–100%) 43% (4–100%) 5% Tubulointerstitial fibrosis   < 25% 26 (76.5%)  25–50% 6 (17.6%)   > 50% 2 (5.9%)

Table 3 Magnetic resonance elastography characteristics of all patients and their subgroups as CRPI and Non-CRPI patients

MRE Magnetic resonance elastography, kPa Kilopascal, CRPI Chronic renal parenchymal injury

Sequences Results mean (± SD) or median (Min– Max)

Distribution

All Patients CRPI Non-CRPI P

MRE (kPa)  Whole

Kidney 3.78

(± 1.26) 3.13

(± 0.89) 4.23

(± 1.30) P < 0.05

 Cortex 3.63 (± 1.25)

3.20 (± 1.15)

3.94 (± 1.26)

P > 0.05

 Medulla 4.77 (± 2.03)

3.73 (± 1.54)

5.50 (± 2.04)

P < 0.01

Table 4 Correlation analysis of MRE-derived stiffness values and clinical parameters

MRE Magnetic resonance elastography

Groups of Correlation Spearman Rho P Value

Whole kidney MRE-derived stiffness and  Urine albumin to creatinine 0.418 0.02  Urine protein to creatinine 0.396 0.02  24-h protein in urine 0.620 0.01  Serum albumin − 0.518 < 0.01  Serum protein − 0.610 < 0.01  Serum creatinine − 0.357 0.03

Cortex MRE-derived stiffness and  Urine albumin to creatinine 0.378 0.03  Urine protein to creatinine 0.343 0.04  24-h protein in urine 0.576 0.01  Serum albumin − 0.458 < 0.01  Serum protein − 0.568 < 0.01

Medulla MRE-derived stiffness and  Urine albumin to creatinine 0.380 0.03  Urine protein to creatinine 0.384 0.03  24-h protein in urine 0.644 < 0.01  Serum albumin 0.427 0.01  Serum protein − 0.530 < 0.01  Serum creatinine − 0.349 0.03

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(r = − 0.295; P = 0.09), segmental glomerulosclero- sis (r = − 0.270; P = 0.12), nor tubulointerstitial fibrosis (r = − 0.93; P = 0.603). Regarding the group of patients with evidence of CRPI, there was no correlation observed

between any stiffness value and histopathological parameter except for the negative correlation between confidence map MRE-derived stiffness and segmental glomerulosclerosis (r = − 0.630, P = 0.016). No correlation between MRE- derived stiffness values and histopathological parameters was seen in the group of patients lacking evidence of CRPI. The relationship between MRE-derived stiffness and fibrosis is shown in Table 5 and Figs. 4, 5, and 6, 7.

Discussion

In this study, we have shown that kidney stiffness measured via MRE decreases with increasing extent of glomerulo- sclerosis and tubulointerstitial fibrosis as well as with clin- icopathological evidence of CRPI. To our knowledge, this is the first study to show a negative correlation between

Table 5 Correlation analysis of MRE-derived stiffness values and histopathological parameters

MRE Magnetic resonance elastography

Groups of Correlation Spearman Rho P Value

Whole kidney MRE-derived stiffness and  Global glomerulosclerosis − 0.391 0.022

Medulla MRE-derived stiffness and  Global glomerulosclerosis − 0.412 0.015  Segmental glomerulosclerosis − 0.361 0.036  Tubulointerstitial fibrosis − 0.401 0.019

Fig. 4 Whole Kidney MRE- Derived Stiffness vs. Global Glomerulosclerosis

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Fig. 5 Medulla MRE-Derived Stiffness vs. Global Glomerulo- sclerosis

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MRE-derived stiffness and evidence of CRPI in patients with various causes of glomerulonephritis and AA amyloi- dosis. Regarding all 34 patients, MRE-derived stiffness val- ues correlated negatively with histopathological parameters of fibrosis consistent with decreased stiffness of kidneys with worsening renal functions. Our findings are similar to Brown et al.’s [5] study in which MRE-derived stiffness val- ues decrease as kidney fibrosis worsens in diabetic nephro- pathic kidneys. Contrary to ours and Brown et al.’s findings, several studies [22, 24, 25] demonstrated that MRE-derived stiffness increases with worsening renal fibrosis in renal allo- grafts, similar to liver fibrosis [28]. Lastly, Han et al. [29] using MR elastography showed that renal tissue stiffness in patients with CKD significantly increases as CKD stage progresses although it decreases in stage 5 CKD.

Tissue stiffness is not only affected from fibrosis but is also affected from hydrostatic pressures as well. Brown et al. used arterial spin labeling MRI to assess cortical blood flow contributing to kidney stiffness. They discovered that decrease in stiffness with progression of diabetic nephropa- thy was caused by reduced turgor stiffness due to decrease in cortical blood flow. Han et al. [29] also linked their finding to the reduction in renal blood flow that occurs in patients with stage 5 CKD. Since we did not perform arterial spin labeling MRI, we could not assess whether our findings were also caused by diminished cortical blood flow.

Considering that the kidney receives up to 20% of the cardiac output [30], effect of hydrostatic forces on kidney stiffness is more prominent than it is in liver. Alongside these factors, the deeper localization of the kidneys brings

Fig. 6 Medulla MRE-Derived Stiffness vs. Segmental Glo- merulosclerosis

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Fig. 7 Mean Medulla MRE- Derived Stiffness vs Tubuloint- erstitial Fibrosis

<25%, 5.17

25-50%, 3.66 >50%, 2.99

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different properties in comparison to the liver when mechan- ical vibrations are applied.

We have shown statistically significant negative correla- tions between fibrosis and MRE-derived stiffness acquired from whole kidney and medulla. In contrast to this finding, correlation between cortex-derived MRE stiffness and extent of global glomerulosclerosis was weak and statistically insignificant; moreover, there was no relation with extent of segmental glomerulosclerosis and tubulointerstitial fibrosis. Considering that the cortex constitutes a thin part of the kidney, it is hard to differentiate the wave propagation and mechanical properties of the cortex from the medulla. This problem was also underlined by Brown et al. [5] and Lee et al. [22], stating that using 3D MRE or higher frequency vibration could overcome this problem. We attributed the lack of correlation in our study to the fact that we used 2D and relatively low frequency MRE.

Our study is the first to compare MRE stiffness of kidneys with and without evidence of CRPI in glomerulonephritis patients. For the first time, we have revealed that chronically injured kidneys became significantly softer in the glomeru- lonephritis and AA amyloidosis patient cohort.

Although creatinine is not an accurate marker of fibro- sis, all three histopathological parameters of fibrosis cor- related positively with creatinine in our patient cohort. This is expected given the fact that our cohort was devoid of patients with acute tubulointerstitial injury or severe glo- merular injury characterized by extracapillary proliferation. Similar to the histopathological correlations, whole kidney and medulla MRE-derived stiffness values correlated nega- tively with creatinine, further suggesting kidney stiffness decreases as kidney functions deteriorate in patients with glomerulonephritis and AA amyloidosis. Lack of correlation between cortex MRE-derived stiffness and creatinine may be caused by the limited capability of MRE to distinguish mechanical properties of cortex and medulla.

Our study has many novel findings and strengths. Most important aspect of this study is the fact that all 34 patients had histopathological scores matched with their MRE- derived stiffness values and clinical parameters. Another strength of this study is that we grouped the patients according to chronicity and assessed relation between chronicity and stiffness. We also acknowledge some limi- tations. Most important limitation of this study is that it only consisted of 34 patients with unequal distribution of patient subgroups, leading to lack of generalizability to each subgroup. While 2D MRE is used in clinical practice to assess liver fibrosis and previous studies conducted in kidneys also demonstrated the feasibility of 2D MRE, it is acknowledged that 3D MRE is superior to 2D MRE by minimizing quantitative artifacts related to varying direc- tionality of wave propagation, which is not commercially available. We also did not weight each patient thus could

not report the patients’ BMIs. Although we did not have any marginally weighted (i.e., underweight or morbid obese) patient, differences in body fat could bring expla- nation to different wave propagation characteristics.

As determinants of fibrosis (i.e., fibrosis, hydrostatic pressure, and blood flow) vary between various disease processes of different organs, findings of this study are not generalizable to other diseases and organs and only applies to primary glomerulopathy/glomerulonephritis and AA amyloidosis of the kidney. However, future studies may bring further insight to the use of MRE measurements with specific cut-offs according to the different causes of glomerular diseases. This may be studied in the future with evolving MR technology.

Since fibrosis is the end result of various insults to kid- ney [2], quantification of fibrosis could potentially help identify high-risk patients whose routine kidney function markers such as creatinine are not markedly impaired yet. Considering evolving novel anti-fibrotic therapies [1, 31, 32], importance of detecting fibrotic burden becomes more remarkable. Kidney biopsy is the gold standard to assess fibrosis [6]. Alongside its disadvantages related to inva- siveness, patchy distribution of fibrosis within kidneys and small sample amounts lead to flawed fibrosis burden assessment, thus necessitating development of non-inva- sive and more accurate means. We believe that future stud- ies will elucidate and quantify factors associated with stiff- ness measured via MR elastography and increase its utility as well as quality. Alternative kidney function assessment methods such as MR elastography will reveal chronicity and extent of renal fibrosis superior to current methods and will replace kidney biopsy. This will help eliminate controversies regarding biopsy need and immunosuppres- sive drug use by better defining patients that will benefit from interventions and drugs.

In conclusion, we have demonstrated the feasibility of MRE to assess fibrosis and chronicity in patients with primary glomerulonephritis and AA amyloidosis. Kidney stiffness decreases with chronicity and worsening kidney functions as indicated both by histopathological markers and creatinine levels.

Acknowledgements This study was supported by hacettepe üniversi- tesi with Grant No. TTU 2019-17871.

Author contributions İ.S.İ, A.S., M.K., and M.A. designed the study, A.T.G., C.C., C.Ö. M.Ü.K. T.Y., R.Y., B.A, and Y.E collected the data, A.T.G., İ.S.İ, A.S., M.K., and M.A. analyzed the data; A.T.G., İ.S.İ, A.S., M.K., and M.A. wrote the paper.

Declarations

Conflict of interest The authors declare that they have no conflict of interest.

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