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\def\RunningAuthor{Abdullah H Drewil et al.}
\firstPage{3073}
\articleType{Original Article}
\receivedDate{10 Nov 2020}
\acceptedDate{19 Dec 2020}
\revisedDate{13 Dec 2020}
\journalVolume{2020, 11 (SPL4)}
\journalDoi{ijrps.v11iSPL4.4608}
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\title{\textbf{Evaluation of Indoxyl }\textbf{Sulfate} \textbf{ in Chronic Kidney Disease associated with Left Ventricular Hypertrophy}}
\author{Abdullah~H~Drewil\textsuperscript{*}\textsuperscript{1},  
            Mohammed~A~Al-Bayati\textsuperscript{1}, 
            Arif~S~Malik\textsuperscript{2}~\\[5pt]{\textsuperscript{1}Department of Chemistry and Biochemistry, College of Medicine/ Al-Nahrain University, Baghdad 64074, Iraq}~\\{\textsuperscript{2}Department of Nephrology, College of Medicine/ Al-Nahrain University, Baghdad 64074, Iraq}}

\begin{abstract}
Chronic kidney disease CKD is widely prevalent globally and Left ventricular hypertrophy (LVH) is very common among CKD patients and contributes to CV mortality which can be monitored by measuring the levels of indoxyl sulfate (IS). Study the correlation of indoxyl sulphate and the degree of left Ventricular hypertrophy in CKD patients. A case control study was done on 90 patients with Chronic kidney disease CKD, 45 of them with who were recruited the Imamian Al-Khadhemian Medical City and Baghedad Hospital, Baghdad, Iraq between January, and September 2020. The levels of indoxyl sulfate and other parameters were measured in the serum of Left ventricular hypertrophy (LVH) and compared with those with a no evidence of LVH) who considered as BMI and sex matched control group. Indoxyl sulfate (IS) levels in patients with chronic kidney disease and an evidence of lift ventricular hypertrophy (LVH-CKD) group were significantly (p=0.001) higher than those of patients with chronic kidney disease without an evidence of lift ventricular hypertrophy (NLVH-CKD) and IS levels were associated significantly with the severity of LVH. The possibility to use IS as a marker for early diagnosis of LVH in patients suffered from CKD and it can be used to determine the severity of LVH in those patients.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Indoxyl Sulfate,\newline Chronic Kidney Disease (CKD),\newline Left Ventricular Hypertrophy (LVH)
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Abdullah~H~Drewil~\\ Phone:\ 00 964 7739299707~\\  Email:\ abdullhha4@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
Chronic kidney disease is widely prevalent globally that affects approximately 15\% of the general population \unskip~\citep{989767:21283104}. Chronic kidney disease prevalence showed to be increased progressively with age \unskip~\citep{989767:21283107}. Patients suffering from CKD were more likely to die because of cardiovascular disease (CVD) rather than to reach to the end stage of kidney disease with the receiving of dialysis \unskip~\citep{989767:21283105}. In CKD patients, Left ventricular hypertrophy (LVH) is considered as one of the most common complications and contributed to cardiovascular mortality as it causes congestive heart failure, arrhythmia or sudden death. The traditional definition and determination of LVH was performed by echo cardiogram, but magnetic resonance imaging (MRI) become the recently used tool to define LVH which revealed that it is more prevalent in patients with CKD than previously thought \unskip~\citep{989767:21283098}. Although There is evidence that cardiovascular complications in CKD like LVH followed by infarction and stroke \unskip~\citep{989767:21283106} are caused by conventional risk factors, such as anemia and elevated blood pressure, CKD-specific 


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\makeatother 
\caption{\boldmath {Age and BMI levels in all studied groups.}}
\label{f-2ac4fb14ddab}
\end{figure}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {General characteristics of the study groups.} }
\label{tw-63ab2b20409d}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.25990000000000002\linewidth-2\tabcolsep}p{\dimexpr.18692000000000007\linewidth-2\tabcolsep}p{\dimexpr.19264\linewidth-2\tabcolsep}p{\dimexpr.2017\linewidth-2\tabcolsep}p{\dimexpr.15884000000000002\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor} &
   &
  \cAlignHack \textbf{LVH-CKD} &
  \cAlignHack \textbf{NLVH-CKD} &
  \cAlignHack \textbf{P value}\\
\tblmidrule 
\textbf{Number of cases} &
  N &
  \cAlignHack 45 &
  \cAlignHack 45 &
  \cAlignHack \\
\textbf{Gender} &
  Male &
  \cAlignHack 32 &
  \cAlignHack 33 &
  \cAlignHack 0.814\\
 &
  Female &
  \cAlignHack 13 &
  \cAlignHack 12 &
  \\
\textbf{Diabetes Mellitus } &
  DM &
  \cAlignHack 24 &
  \cAlignHack 17 &
  \cAlignHack 0.138\\
\textbf{(DM)} &
  Non-DM &
  \cAlignHack 21 &
  \cAlignHack 28 &
  \\
\textbf{Hypertension \textbf{(HTN)}} &
  HTN &
  \cAlignHack 40 &
  \cAlignHack 5 &
  \cAlignHack {\textless}0.001\\
 &
  Non-HTN &
  \cAlignHack 15 &
  \cAlignHack 30 &
  \\
\textbf{BP} &
  Pulse pressure &
  \cAlignHack 66.69\ensuremath{\pm}8.1 &
  \cAlignHack 46.44\ensuremath{\pm}5.96 &
  \cAlignHack {\textless}0.001\\
 &
  Systolic &
  \cAlignHack 176.16\ensuremath{\pm}13.05 &
  \cAlignHack 134.47\ensuremath{\pm}25.01 &
  \cAlignHack {\textless}0.001\\
 &
  Diastolic &
  \cAlignHack 103.2\ensuremath{\pm}17.63 &
  \cAlignHack 80.53\ensuremath{\pm}28.42 &
  \cAlignHack {\textless}0.001\\
\textbf{Address} &
  Kerkh &
  \cAlignHack 15 &
  \cAlignHack 16 &
  \cAlignHack 0.844\\
 &
  Resafa &
  \cAlignHack 22 &
  \cAlignHack 23 &
  \\
 &
  Outskirts  &
  \cAlignHack   8 &
  \cAlignHack 6 &
  \\
\textbf{Smoking} &
  Chronic &
  \cAlignHack 7 &
  \cAlignHack 0 &
  \cAlignHack 0.012\\
 &
  Current &
  \cAlignHack 7 &
  \cAlignHack 4 &
  \\
 &
  ex-smoker &
  \cAlignHack 18 &
  \cAlignHack 30 &
  \\
 &
  Never &
  \cAlignHack 13 &
  \cAlignHack 11 &
  \\
\textbf{Causes of CKD} &
  DM &
  \cAlignHack 12 &
  \cAlignHack 10 &
  \cAlignHack 0.036\\
 &
  HTN &
  \cAlignHack 20 &
  \cAlignHack 12 &
  \\
 &
  History &
  \cAlignHack 7 &
  \cAlignHack 5 &
  \\
 &
  Other &
  \cAlignHack 6 &
  \cAlignHack 18 &
  \\
\textbf{Age (year)} &
  - &
  \cAlignHack 37.04\ensuremath{\pm}11.47 &
  \cAlignHack 39.56\ensuremath{\pm}12.18 &
  \cAlignHack 0.317\\
\textbf{BMI (Kg/m\ensuremath{^{2}})} &
  - &
  \cAlignHack 26.32\ensuremath{\pm}3.98 &
  \cAlignHack 26.29\ensuremath{\pm}3.64 &
  \cAlignHack 0.967\\
\textbf{CKD-duration} &
  - &
  \cAlignHack 28.23\ensuremath{\pm}25.41 &
  \cAlignHack 22.59\ensuremath{\pm}25.68 &
  \cAlignHack 0.3\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
factors mineral derangement like calcium and phosphorus \unskip~\citep{989767:21283103,989767:21283110,989767:21283108}. However, LVH is considered as a possible cause for an increased rate of mortality in patients with an advanced CKD \unskip~\citep{989767:21283115}.

LVH in patients with CKD known also as uremic cardiomyopathy as it occurs even in the absence of anemia, hypertension or other conventional risk factors \unskip~\citep{989767:21283101}. Furthermore correction of some risk factors like anemia did not result in prevention of LVH \unskip~\citep{989767:21283102}. Indoxyl sulfate is considered as a one of the most important uremic solute that derived from bacterial action on dietary protein specifically tryptophan. In CKD patients, the diminished GFR lead to a reduction in the rate of IS excretion, that causes a gradual elevation in serum IS levels with both pre- and post-dialysis which associated with CVD. It was reported that IS affect CVS by its role in the development of atherosclerosis due to its induction effect vascular endothelial cell that lead to a dysfunction as a consequence of enhancing oxidative stress \unskip~\citep{989767:21283113}.
    
\section{Materials and Methods}
This case control study was carried out on a 90 patients age range from 18 to 60 years, consist of patients diagnosed as CKD, all this patient has LVH compare to 45 patient have CKD only as control were enrolled serially in the study. Age, gender and body mass index (BMI) matched control subjects were taken from the same socioeconomic population of cases. All persons in control group were having CKD but not LVH. 


\bgroup
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\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/b5df8571-5806-4c0c-8d4d-5bd81c476bb7-upicture-12.png}{\includegraphics{images/b5df8571-5806-4c0c-8d4d-5bd81c476bb7-upicture-12.png}}{}
\makeatother 
\caption{\boldmath {Indoxyl sulfate (IS) levels in all studied groups.}}
\label{f-5cee8c8c2c0b}
\end{figure}
\egroup
All patients subjected to the study were notified and informed about the study goals. All biochemical tests were performed free of charges for all participants and all results obtained were provided to them. All patients were attended from the Imamian Al-Khadhemian Medical City and Baghedad Hospital. Patients and controls were with a comparable age. The practical part of the study was conducted at Department of Chemistry and Biochemistry, College of Medicine and Middle East Clinical Laboratory, Baghdad- Iraq. The study has approved by the Institutional Review Board (IRB) of the College of Medicine, University of Al-Nahrain, Baghdad, Iraq. In addition, an informed written consent for participation in the study was signed by investigated subjects according to the Helsinki principles.

\textbf{Sample collection and preparation}

Samples of seven milliliters of blood were collected from all participants in plain tube and left to clot for 30 min at room temperature then were centrifuged at 4000rpm (1252 x) g for 10 min, the separated sera were divided into small aliquots and store at (-20\ensuremath{^{o}}C) until assayed for the evaluation of Indoxyl sulphate (IS). IS levels were estimated by enzyme-linked immunosorbent assays (ELISAs) with kits obtained from Elabscience (USA) according to the manufacturer instructions.

\textbf{Statistical analysis}

Results obtained in the present study were analyzed using the SPSS software 20. Numerical variables were expressed as mean \ensuremath{\pm} SD and all statistical comparisons were made by means of independent t-test and ANOVA test with P \ensuremath{\leq }0.05 was considered statistically significant. Categorical variables were expressed as numbers and analyzed by cross tabulation to assess the frequency and percentage of each variable among studied groups. The correlation was done between all parameters using Pearson correlation test and Chi square to test the relationships between categorical variables with the measurement of Phi that is considered as a chi-square based measure of association to indicate the strength of the association (given that values ranged from 0-0.5 considered as weak association while values above 0.5 considered as strong association) in addition to p values. The normality of distribution was checked using Shapiro- Wilk and Kolmogorov- Smirnov tests.
    
\section{Results and Discussion}
In this study, some characteristics of the studied groups summarized in Table~\ref{tw-63ab2b20409d} and Figure~\ref{f-2ac4fb14ddab} that assessed by analyzing questionnaire answered by a direct interview with all subjects as indicated in appendix 1.

Table~\ref{tw-63ab2b20409d} showed that the group of patients with chronic kidney disease and an evidence of lift ventricular hypertrophy (LVH-CKD) were age, sex, BMI, and address matched to those with chronic kidney disease without an evidence of lift ventricular hypertrophy (NLVH-CKD). Moreover, there were non significant differences in a duration of CKD and incidence of DM between the two studied groups 

whereas significant differences were obtained in the smoking habit, causes of CKD, pulse pressure, systolic and diastolic blood pressure in addition to hypertension incidence between the studied groups. According to results illustrated in Table~\ref{tw-57949f6e9523} and Figure~\ref{f-5cee8c8c2c0b}, Indoxyl sulfate (IS) levels in patients with chronic kidney disease and an evidence of lift ventricular hypertrophy (LVH-CKD) group were significantly (p=0.001) higher than those of patients with chronic kidney disease without an evidence of lift ventricular hypertrophy (NLVH-CKD). Results postulated in Table~\ref{tw-57949f6e9523} also revealed that there were non-significant differences between male and female patients in the levels of Indoxyl sulfate (IS).

On the other hand, Indoxyl sulfate (IS) levels in diabetic group were significantly higher than those of non-diabetic group\textbf{\space }whereas\textbf{\space }non-significant differences were obtained between hypertensive and normotensive patients in the levels of Indoxyl sulfate (IS). Furthermore, there were non-significant differences between smoking habit patients groups in the levels of Indoxyl sulfate (IS). Geographical distribution showed non-significant effect on the levels of Indoxyl sulfate (IS). Results demonstrated in Table~\ref{tw-57949f6e9523} revealed that the levels of Indoxyl sulfate (IS) were significantly affected by the causes of CKD and showed a significant difference among all studied subgroups given that patients suffered from CKD as a result of DM showed the highest levels of IS followed by patients with a family history of CKD.

Results illustrated in Table~\ref{tw-a3eb9009dd1d} revealed non significant differences in levels of Indoxyl sulfate among


\begin{table*}[!htbp]
\caption{\boldmath {Comparison between all studied groups in the levels of Indoxyl sulfate (IS).} }
\label{tw-57949f6e9523}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.27395\linewidth-2\tabcolsep}p{\dimexpr.17740000000000002\linewidth-2\tabcolsep}p{\dimexpr.3470499999999999\linewidth-2\tabcolsep}p{\dimexpr.20160000000000004\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{2}{p{\dimexpr(.45135000000000005\linewidth-2\tabcolsep)}}{\cAlignHack \textbf{Group}} & \cAlignHack \textbf{Mean \ensuremath{\pm} SD} & \cAlignHack \textbf{P\ensuremath{^{a}}}\\
\tblmidrule 
\cAlignHack LVH-CKD &
  (n=45) &
  \cAlignHack 767.98 \ensuremath{\pm} 356.59 &
  \cAlignHack 0.001\\
\cAlignHack NLVH-CKD &
  (n=45) &
  \cAlignHack 551.97 \ensuremath{\pm} 575.35 &
  \cAlignHack \\
\cAlignHack Male &
  (n=65) &
  \cAlignHack 664.31 \ensuremath{\pm} 511.02 &
  \cAlignHack 0.89\\
\cAlignHack Female &
  (n=25) &
  \cAlignHack 648.7 \ensuremath{\pm} 5368.79 &
  \cAlignHack \\
\cAlignHack DM &
  (n=41) &
  \cAlignHack 789.86 \ensuremath{\pm} 548.58 &
  \cAlignHack 0.01\\
\cAlignHack Non-DM &
  (n=49) &
  \cAlignHack 543.77 \ensuremath{\pm} 376.29 &
  \cAlignHack \\
\cAlignHack HTN &
  (n=55) &
  \cAlignHack 674.65 \ensuremath{\pm} 381.27 &
  \cAlignHack 0.715\\
\cAlignHack Non-HTN &
  (n=35) &
  \cAlignHack 636.92 \ensuremath{\pm} 596.58 &
  \cAlignHack \\
\cAlignHack Non smoker &
  (n=24) &
  \cAlignHack 645.6 \ensuremath{\pm} 403.78 &
  \cAlignHack 0.819\\
\cAlignHack Ex-smoker &
  (n=48) &
  \cAlignHack 679.87 \ensuremath{\pm} 537.42 &
  \cAlignHack \\
\cAlignHack Current smoker &
  (n=11) &
  \cAlignHack 548.91 \ensuremath{\pm} 393.33 &
  \cAlignHack \\
\cAlignHack Chronic smoker &
  (n=7) &
  \cAlignHack 747.37 \ensuremath{\pm} 386.66 &
  \cAlignHack \\
\cAlignHack Kerkh  &
  (n=31) &
  \cAlignHack 602.03 \ensuremath{\pm} 444.22 &
  \cAlignHack 0.629\\
\cAlignHack Resafa &
  (n=45) &
  \cAlignHack 673.7 \ensuremath{\pm} 513.31 &
  \cAlignHack \\
\cAlignHack Outskirts &
  (n=14) &
  \cAlignHack 744.18 \ensuremath{\pm} 416.6 &
  \cAlignHack \\
\cAlignHack DM &
  (n=22) &
  \cAlignHack 1000.99 \ensuremath{\pm} 626.87 &
  \cAlignHack 0.001\\
\cAlignHack HTN &
  (n=32) &
  \cAlignHack 60.18 \ensuremath{\pm} 325.32 &
  \cAlignHack \\
\cAlignHack History &
  (n=12) &
  \cAlignHack 576.07 \ensuremath{\pm} 296.25 &
  \cAlignHack \\
\cAlignHack Other &
  (n=24) &
  \cAlignHack 469.06 \ensuremath{\pm} 409.19 &
  \cAlignHack \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Comparison between CKD stages in the levels of Alpha-Klotho (\ensuremath{\alpha }Klotho), Indoxyl sulfate (IS) and Malondialdehyde (MDA).} }
\label{tw-a3eb9009dd1d}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.3644\linewidth-2\tabcolsep}p{\dimexpr.39349999999999994\linewidth-2\tabcolsep}p{\dimexpr.2421\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack \textbf{Group} & \cAlignHack \textbf{mean \ensuremath{\pm} SD} & \cAlignHack \textbf{P\ensuremath{^{a}}}\\
\tblmidrule 
\cAlignHack \textbf{CKD stages} &
   &
  \\
\cAlignHack Stage 2 (n= 2) &
  \cAlignHack 341.99 \ensuremath{\pm} 132.03 &
  \cAlignHack 0.106\\
\cAlignHack Stage 3a (n=12) &
  \cAlignHack 369.31 \ensuremath{\pm} 227.02 &
  \cAlignHack \\
\cAlignHack Stage 3b (n=8) &
  \cAlignHack 573.71 \ensuremath{\pm} 415.78 &
  \cAlignHack \\
\cAlignHack Stage 4 (n=24) &
  \cAlignHack 777.55 \ensuremath{\pm} 637.13 &
  \cAlignHack \\
\cAlignHack Stage 5 (n=44) &
  \cAlignHack 705.25 \ensuremath{\pm} 407.86 &
  \cAlignHack \\
\cAlignHack \textbf{LVH severity} &
   &
  \\
\cAlignHack Mild (n=35) &
  \cAlignHack 706.09 \ensuremath{\pm} 327.98 &
  \cAlignHack 0.028\\
\cAlignHack Severe (n=10) &
  \cAlignHack 984.60 \ensuremath{\pm} 385.05 &
  \cAlignHack \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
patients with different CKD stages while significant elevations were obtained in Indoxyl sulfate levels in CKD patients with severe LVH when compared with those of CKD patients with mild LVH. Results illustrated in Table~\ref{tw-78468d5e85da} revealed that the levels of urea, creatinine, uric acid, calcium, potassium, phosphate and fasting blood sugar were significantly elevated in patients with chronic kidney disease with an evidence of lift ventricular hypertrophy (LVH-CKD) and those without an evidence of lift ventricular hypertrophy (NLVH-CKD). On the other hand, levels of estimated glomerular filtration rate (eGFR) and hemoglobin were reduced significantly in LVH-CKD patients than those of NLVH-CKD. Additionally, sodium and chloride levels showed non-significant difference between the studied groups. Results obtained in Table~\ref{tw-0b42ce5a9b46} demonstrated that there were negative significant correlations between the age and BMI whereas all other correlations were non-significant. Data illustrated in Table~\ref{tw-4a04b1226bd5} showed that there were non-significant correlation between both of IS with renal function tests measured. Results illustrated in Table~\ref{tw-14a8ca85feb7} revealed that there were non-significant correlations between Alpha-Klotho (\ensuremath{\alpha }Klotho), Indoxyl sulfate (IS), Malondialdehyde (MDA) levels and the levels of serum ions (Ca, Na, Cl, PO4). Results postulated in Table~\ref{tw-dd497aa62cff} showed that the incidence of LVH was associated significantly with the levels of Indoxyl sulfate (IS). IS showed to be significantly associated with DM and 


\begin{table*}[!htbp]
\caption{\boldmath {Laboratory characteristics in patients with chronic kidney disease and an evidence of lift ventricular hypertrophy (LVH-CKD) and patients with non LVH-CKD (NLVH-CKD).} }
\label{tw-78468d5e85da}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1919\linewidth-2\tabcolsep}p{\dimexpr.30810000000000002\linewidth-2\tabcolsep}p{\dimexpr.31429999999999996\linewidth-2\tabcolsep}p{\dimexpr.1857\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\textbf{Variable} & \cAlignHack \textbf{LVH-CKD (n=45)} & \cAlignHack \textbf{NLVH-CKD (n=45)} & \cAlignHack \textbf{p-value}\\
\tblmidrule 
Urea &
  \cAlignHack 211.62 \ensuremath{\pm} 67.66 &
  \cAlignHack 115.42 \ensuremath{\pm} 50.46 &
  \cAlignHack {\textless}0.001\\
Creatinine &
  \cAlignHack 6.80 \ensuremath{\pm} 2.59 &
  \cAlignHack 2.99 \ensuremath{\pm} 1.92 &
  \cAlignHack {\textless}0.001\\
eGFR &
  \cAlignHack 11.57 \ensuremath{\pm} 6.68 &
  \cAlignHack 31.84 \ensuremath{\pm} 16.31 &
  \cAlignHack {\textless}0.001\\
UA &
  \cAlignHack 9.03 \ensuremath{\pm} 2.13 &
  \cAlignHack 4.94 \ensuremath{\pm} 1.95 &
  \cAlignHack {\textless}0.001\\
Ca &
  \cAlignHack 10.92 \ensuremath{\pm} 1.52 &
  \cAlignHack 9.70 \ensuremath{\pm} 0.84 &
  \cAlignHack {\textless}0.001\\
Na &
  \cAlignHack 138.88 \ensuremath{\pm} 5.39 &
  \cAlignHack 140.51 \ensuremath{\pm} 4.18 &
  \cAlignHack 0.114\\
K &
  \cAlignHack 4.78 \ensuremath{\pm} 0.75 &
  \cAlignHack 4.18 \ensuremath{\pm} 0.39 &
  \cAlignHack {\textless}0.001\\
Cl &
  \cAlignHack 101.44 \ensuremath{\pm} 5.25 &
  \cAlignHack 100.06 \ensuremath{\pm} 4.53 &
  \cAlignHack 0.186\\
PO4 &
  \cAlignHack 5.34 \ensuremath{\pm} 0.83 &
  \cAlignHack 4.72 \ensuremath{\pm} 0.83 &
  \cAlignHack 0.001\\
HB &
  \cAlignHack 8.79 \ensuremath{\pm} 1.58 &
  \cAlignHack 11.74 \ensuremath{\pm} 1.41 &
  \cAlignHack {\textless}0.001\\
FBS &
  \cAlignHack 161.80 \ensuremath{\pm} 60.14 &
  \cAlignHack 136.40 \ensuremath{\pm} 47.41 &
  \cAlignHack 0.029\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {The correlations between \ensuremath{\alpha }Klotho, IS, MDA, hemoglobin (HB) andfasting blood sugar (FBS) levels and age, body mass index (BMI) and the duration of CKD in patients with LVH-CKD.} }
\label{tw-0b42ce5a9b46}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.09655714285714286\linewidth-2\tabcolsep}p{\dimexpr.0828857142857143\linewidth-2\tabcolsep}p{\dimexpr.13492857142857142\linewidth-2\tabcolsep}p{\dimexpr.13942857142857145\linewidth-2\tabcolsep}p{\dimexpr.13631428571428577\linewidth-2\tabcolsep}p{\dimexpr.1351285714285714\linewidth-2\tabcolsep}p{\dimexpr.2747571428571429\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor} &  & \cAlignHack \textbf{HB} & \cAlignHack \textbf{Age} & \cAlignHack \textbf{BMI} & \cAlignHack \textbf{FBS} & \cAlignHack \textbf{How long have CKD (months)}\\
\tblmidrule 
IS &
  \cAlignHack r &
  \cAlignHack 0.117 &
  \cAlignHack 0.004 &
  \cAlignHack 0.061 &
  \cAlignHack 0.169 &
  \cAlignHack 0.002\\
 &
  \cAlignHack p &
  \cAlignHack 0.445 &
  \cAlignHack 0.979 &
  \cAlignHack 0.689 &
  \cAlignHack 0.267 &
  \cAlignHack 0.990\\
HB &
  \cAlignHack r &
  \cAlignHack - &
  \cAlignHack 0.144 &
  \cAlignHack -0.124 &
  \cAlignHack -0.055 &
  \cAlignHack 0.017\\
 &
  \cAlignHack p &
  \cAlignHack - &
  \cAlignHack 0.346 &
  \cAlignHack 0.416 &
  \cAlignHack 0.719 &
  \cAlignHack 0.911\\
Age &
  \cAlignHack r &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack -0.446 &
  \cAlignHack 0.011 &
  \cAlignHack 0.118\\
 &
  \cAlignHack p &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack 0.002 &
  \cAlignHack 0.945 &
  \cAlignHack 0.441\\
BMI &
  \cAlignHack r &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack -0.031 &
  \cAlignHack -0.045\\
 &
  \cAlignHack p &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack 0.838 &
  \cAlignHack 0.768\\
FBS &
  \cAlignHack r &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack -0.149\\
 &
  \cAlignHack p &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack 0.329\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
non-significantly associated with the stages of CKD and HTN. Indoxyl sulfate is considered as a one of the most important uremic solute that derived from bacterial action on dietary protein specifically tryptophan. In CKD patients, the diminished GFR lead to a reduction in the rate of IS excretion, that causes a gradual elevation in serum IS levels with both pre and post dialysis which associated with CVD. It was reported that IS affect CVS by its role in the development of atherosclerosis due to its induction effect vascular endothelial cell that lead to a dysfunction as a consequence of enhancing oxidative stress \unskip~\citep{989767:21283113} which is consistent with the results obtained in the present study that showed significant elevation in their levels in LVH-CKD patients in a comparison with those of NLVH-CKD that might be contributed to the reduction in IS excretion as a consequence of impaired renal functions that assessed by the significant elevation in the levels of urea, creatinine, uric acid, calcium, potassium and phosphate with a significant decrease in the estimated glomerular filtration rate in LVH-CKD patients in a comparison with those of NLVH-CKD. Several studies demonstrated that IS levels elevated significantly in CKD patients and the increment is always parallel to the severity of the disease and related to the complications occur such as the cardiovascular complication.


\begin{table*}[!htbp]
\caption{\boldmath {The correlations between Alpha-Klotho (\ensuremath{\alpha }Klotho), Indoxyl sulfate (IS), Malondialdehyde (MDA) and renal function tests (urea, creatinine, uric acid and estimated GFR) inpatients with LVH-CKD.} }
\label{tw-4a04b1226bd5}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.12819999999999999\linewidth-2\tabcolsep}p{\dimexpr.08940000000000003\linewidth-2\tabcolsep}p{\dimexpr.1863\linewidth-2\tabcolsep}p{\dimexpr.1862\linewidth-2\tabcolsep}p{\dimexpr.20019999999999996\linewidth-2\tabcolsep}p{\dimexpr.20970000000000002\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{2}{p{\dimexpr(.2176\linewidth-2\tabcolsep)}}{} & \cAlignHack \textbf{Urea} & \cAlignHack \textbf{Creatinine} & \cAlignHack \textbf{eGFR} & \cAlignHack \textbf{UA}\\
\tblmidrule 
\multicolumn{1}{p{\dimexpr(.12819999999999999\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{IS}} &
  \cAlignHack r &
  \cAlignHack -0.022 &
  \cAlignHack 0.042 &
  \cAlignHack -0.098 &
  \cAlignHack 0.119\\
 &
  \cAlignHack p &
  \cAlignHack 0.888 &
  \cAlignHack 0.783 &
  \cAlignHack 0.521 &
  \cAlignHack 0.437\\
\multicolumn{1}{p{\dimexpr(.12819999999999999\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{Urea}} &
  \cAlignHack r &
  \cAlignHack - &
  \cAlignHack 0.862 &
  \cAlignHack -0.751 &
  \cAlignHack 0.756\\
 &
  \cAlignHack p &
  \cAlignHack - &
  \cAlignHack 0.000 &
  \cAlignHack 0.000 &
  \cAlignHack 0.000\\
\multicolumn{1}{p{\dimexpr(.12819999999999999\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{Creatinine}} &
  \cAlignHack r &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack -0.840 &
  \cAlignHack 0.761\\
 &
  \cAlignHack p &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack 0.000 &
  \cAlignHack 0.000\\
\multicolumn{1}{p{\dimexpr(.12819999999999999\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{eGFR}} &
  \cAlignHack r &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack -0.563\\
 &
  \cAlignHack p &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack 0.000\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {The correlations between Alpha-Klotho (\ensuremath{\alpha }Klotho), Indoxyl sulfate (IS), Malondialdehyde (MDA) and Serum ions (Ca, Na,Cl, PO4).} }
\label{tw-14a8ca85feb7}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1016\linewidth-2\tabcolsep}p{\dimexpr.0806\linewidth-2\tabcolsep}p{\dimexpr.1192\linewidth-2\tabcolsep}p{\dimexpr.11739999999999998\linewidth-2\tabcolsep}p{\dimexpr.11270000000000001\linewidth-2\tabcolsep}p{\dimexpr.1165\linewidth-2\tabcolsep}p{\dimexpr.11649999999999999\linewidth-2\tabcolsep}p{\dimexpr.11820000000000002\linewidth-2\tabcolsep}p{\dimexpr.11729999999999999\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{2}{p{\dimexpr(.1822\linewidth-2\tabcolsep)}}{} & \cAlignHack \textbf{MDA} & \cAlignHack \textbf{IS} & \cAlignHack \textbf{Ca} & \cAlignHack \textbf{Na} & \cAlignHack \textbf{K} & \cAlignHack \textbf{Cl} & \cAlignHack \textbf{PO4}\\
\tblmidrule 
\multicolumn{1}{p{\dimexpr(.1016\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{\ensuremath{\alpha }Klotho}} &
  \cAlignHack r &
  \cAlignHack -0.415 &
  \cAlignHack -0.336 &
  \cAlignHack -0.263 &
  \cAlignHack 0.159 &
  \cAlignHack -0.216 &
  \cAlignHack -0.086 &
  \cAlignHack 0.031\\
 &
  \cAlignHack p &
  \cAlignHack 0.005 &
  \cAlignHack 0.024 &
  \cAlignHack 0.081 &
  \cAlignHack 0.298 &
  \cAlignHack 0.154 &
  \cAlignHack 0.573 &
  \cAlignHack 0.840\\
\multicolumn{1}{p{\dimexpr(.1016\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{MDA}} &
  \cAlignHack r &
  \cAlignHack - &
  \cAlignHack 0.328 &
  \cAlignHack -0.022 &
  \cAlignHack -0.135 &
  \cAlignHack 0.054 &
  \cAlignHack -0.189 &
  \cAlignHack -0.281\\
 &
  \cAlignHack p &
  \cAlignHack - &
  \cAlignHack 0.028 &
  \cAlignHack 0.884 &
  \cAlignHack 0.377 &
  \cAlignHack 0.726 &
  \cAlignHack 0.213 &
  \cAlignHack 0.062\\
\multicolumn{1}{p{\dimexpr(.1016\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{IS}} &
  \cAlignHack r &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack 0.103 &
  \cAlignHack 0.089 &
  \cAlignHack -0.013 &
  \cAlignHack 0.114 &
  \cAlignHack -0.085\\
 &
  \cAlignHack p &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack 0.501 &
  \cAlignHack 0.559 &
  \cAlignHack 0.934 &
  \cAlignHack 0.456 &
  \cAlignHack 0.580\\
\multicolumn{1}{p{\dimexpr(.1016\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{Ca}} &
  \cAlignHack r &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack -0.084 &
  \cAlignHack 0.785** &
  \cAlignHack -0.171 &
  \cAlignHack 0.358*\\
 &
  \cAlignHack p &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack 0.583 &
  \cAlignHack 0.000 &
  \cAlignHack 0.262 &
  \cAlignHack 0.016\\
\multicolumn{1}{p{\dimexpr(.1016\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{Na}} &
  \cAlignHack r &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack -0.262 &
  \cAlignHack 0.051 &
  \cAlignHack 0.032\\
 &
  \cAlignHack p &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack 0.082 &
  \cAlignHack 0.741 &
  \cAlignHack 0.834\\
\multicolumn{1}{p{\dimexpr(.1016\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{K}} &
  \cAlignHack r &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack -0.190 &
  \cAlignHack 0.501**\\
 &
  \cAlignHack p &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack 0.211 &
  \cAlignHack 0.000\\
\multicolumn{1}{p{\dimexpr(.1016\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{Cl}} &
  \cAlignHack r &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack 0.272\\
 &
  \cAlignHack p &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack - &
  \cAlignHack 0.071\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Association of Alpha-Klotho (\ensuremath{\alpha }Klotho), Indoxyl sulfate (IS) and Malondialdehyde (MDA) with the Incidence of LVH, Stages of CKD, DM and HTN.} }
\label{tw-dd497aa62cff}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.09780000000000001\linewidth-2\tabcolsep}p{\dimexpr.13649999999999999\linewidth-2\tabcolsep}p{\dimexpr.2305\linewidth-2\tabcolsep}p{\dimexpr.1863\linewidth-2\tabcolsep}p{\dimexpr.1752\linewidth-2\tabcolsep}p{\dimexpr.1737\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{2}{p{\dimexpr(.2343\linewidth-2\tabcolsep)}}{\textbf{Parameter}} & \cAlignHack \textbf{Incidence of LVH} & \cAlignHack \textbf{Stages of CKD} & \cAlignHack \textbf{DM} & \cAlignHack \textbf{HTN}\\
\tblmidrule 
IS &
  \cAlignHack p-value &
  \cAlignHack 0.03 &
  \cAlignHack 0.077 &
  \cAlignHack 0.01 &
  \cAlignHack 0.715\\
 &
  \cAlignHack Eta\ensuremath{^{2}} &
  \cAlignHack 0.053 &
  \cAlignHack 0.093 &
  \cAlignHack 0.073 &
  \cAlignHack 0.002\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
In addition to involvement in the progression of CKD, a several clinical researches supports the idea that indoxyl sulfate may also contribute to CVD in the CKD patients and proposed that IS levels can be considered as a valuable marker in predicting cardiovascular events in patients with advanced CKD \unskip~\citep{989767:21283099,989767:21283109}. There are a growing number of clinical studies that supports the idea that IS regarded as a crucial factor which contributes to CVD in the CKD, and can be considered as the main link between these diseases \unskip~\citep{989767:21283100,989767:21283109}. 

IS plays a major role in renal-induced systemic inflammation, immune system alteration, and oxidative stress generation in various tissues of the body \unskip~\citep{989767:21283111}. 

Indoxyl sulfate showed non-significant differences in their levels between different genders and also showed that their levels were not affected by hypertension, cigarette smoking and geographic distribution of patients. 

These findings are not fully agree with previous literature which demonstrated that there was a direct link between hypertension in CKD patients and IS levels as it seems to play modulatory roles in some cellular pathways in hypertensive rats through reducing Klotho expression \unskip~\citep{989767:21283114,989767:21283112} which is consistent with the results discussed above about the role of Klotho in the cardiovascular complications of CKD, So, previous researches demonstrated that IS effect indirectly on blood pressure and the incidence of HTN via Klotho expression reduction expression \unskip~\citep{989767:21283114}.
    
\section{Conclusions}
Inoxyl sulfate can be used as a marker for early diagnosis of LVH in patients suffered from CKD and it can be used to determine the severity of LVH in those patients.

\textbf{Funding Support}

The authors declare that they have no funding support for this study.

\textbf{Conflict of Interest}

The authors declare that they have no conflict of interest for this study.
    

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