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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2018  |  Volume : 29  |  Issue : 3  |  Page : 578-585
Pulmonary function tests and plasma nitric oxide levels in pediatric hemodialysis


Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig, Egypt

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Date of Submission13-May-2017
Date of Decision12-Jul-2017
Date of Acceptance12-Jul-2017
Date of Web Publication28-Jun-2018
 

   Abstract 

The relationships between the lungs and the kidneys are clinically important; however, the impact of nitric oxide (NO) on respiratory function in renal patients is less known. The aim of this study is to evaluate pulmonary function tests (PFTs), NO level and their correlation in children on treatment with hemodialysis (HD) for the end-stage renal disease. This study was performed among 20 patients on regular HD and 20 controls. Participants were subjected to clinical examination, and pulmonary function evaluation was performed using spirometry. The following parameters were obtained as follows: forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), Tüffenau index (FEV1/%FVC), (FEF25%-75%), and peak expiratory flow. Spirometry was carried out before and after HD sessions, and at the same time of clinical assessments, blood samples were taken to measure arterial-blood gas (ABG) and NO levels. There was the statistically significant difference between patient and control groups regarding NO and all PFTs except FEV1/FVC. There was no statistically significant correlation between NO and biological parameters in both cases and controls, but there was negative although the statistically not significant correlation between the PFTs, ABG, and duration of dialysis in the case group. There was statistically significant negative correlation between NO and some PFTs in case group; also the effect of dialysis on pulmonary functions tests and NO levels were only on the FVC of patients which significantly improved. Postdialysis blood gases remained normal among children on HD. NO may be involved in the deterioration of pulmonary function, and therefore, we feel that it can be used as a marker of clinical deterioration.

How to cite this article:
Youssef DM, Shokry DM, Elbehidy RM, Mohammed Khedr MK. Pulmonary function tests and plasma nitric oxide levels in pediatric hemodialysis. Saudi J Kidney Dis Transpl 2018;29:578-85

How to cite this URL:
Youssef DM, Shokry DM, Elbehidy RM, Mohammed Khedr MK. Pulmonary function tests and plasma nitric oxide levels in pediatric hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2022 May 17];29:578-85. Available from: https://www.sjkdt.org/text.asp?2018/29/3/578/235174

   Introduction Top


Respiratory complications of chronic renal fai-lure include pulmonary edema, fibrinous pleuritis, pulmonary calcification, and a predisposition to tuberculosis.[1] Impaired pulmonary function in patients on hemodialysis (HD) may be caused by an underlying pulmonary disease; however, the impact of uremia and the effects of HD treatment are not well understood.[2]

Nitric oxide (NO) is an important signaling and effector molecule that plays critical roles in a remarkable array of essential biological processes, ranging from neurotransmission and the control of vascular tone to apoptosis and inflammation.[3] Endogenous NO may have a key role in many physiological and patho-physiological events in the lung. It appears to be important in neural bronchodilator and vasodilator mechanisms, in the regulation of airway and pulmonary blood flow, and in immune defense. When produced in low concentrations by constitutive NO synthase (cNOS) it appears to have a generally beneficial role, but when produced in large amounts by inducible NO synthase (iNOS) it may result in increased inflammatory responses and tissue damage, suggesting that NO may be involved in the pathophysiology of several pulmonary diseases.[4]

There are only a small number of studies which investigated effects of NO on spiro-metry parameters in patients with end-stage renal disease (ESRD) treated with HD especially children. The aim of this study is to evaluate pulmonary function tests (PFTs), NO level and their correlation to each other in children on treatment with HD for ESRD compared to healthy controls, and to evaluate effect of HD on these parameters.


   Subjects and Methods Top


This is a cross-sectional, case–control study and was approved from the Ethical Committee of Faculty of Medicine, Zagazig University. Written informed consent was obtained from the study participants (control group + patient group and their parents). This consent involved providing detailed information about the study. The study was performed among patients on HD for ESRD at the in Nephrology Unit, Pediatrics Department, Zagazig University Hospitals, Sharkia, Egypt. The participants who were eligible and willing to participate in the study were subjected to the following procedures; complete history taking including age, sex, weight and vaccination history, anthropometric measurements, and spirometry test for assessment of pulmonary function. Blood samples were collected by a technician in tubes containing an anticoagulant, from arterial dialysis line in HD patients and from an arterial puncture in healthy controls and analyzed in the laboratory to measure arterial-blood gas (ABG) and NO; for patients group, we did all tests twice just before dialysis session and just after the end. Tests were done once for the control group.

Forty participants participated in this study; they were organized into two groups, one patient group and one control group. These were selected from the date of starting the study in November 2014 to fulfilling the sample size in October 2015. The sample was selected randomly from the patient on HD for ESRD at our unit. Case group was 20 patients on three to four hours HD three times per week for ESRD. Their age ranged from 0.5 to 11 years with a mean of 4.6 years. These individuals had been undergoing dialysis regularly for at least six months and were stable from a clinical and surgical point of view and were also under regular clinical follow-up. Patients with renal failure on regular HD three times/week; patients with adequate dialysis urea reduction ratio >60%, both sexes, all social and educational classes were included in the study. We excluded patients who had any un-controlled heart disease (congenital or valvular heart disease), liver disease (cirrhosis or im-paired liver function), lung disease (asthma, interstitial or obstructive lung disease), central nervous system disease (myopathy andcerebral palsy) or metabolic disease, renal failure secondary to systemic disease (e.g., systemic lupus erythematosus) or refusal of participation. Control group consisted of 20 age-matched and sex-matched apparently healthy controls selected from an outpatient clinic in Zagazig university hospital.

Pulmonary function tests (for both patients and controls)

A sitting position was generally used at the time of testing to prevent the risk of falling and injury in the event of a syncopal episode; although, PFTs can be performed in the standing position. Patients are advised not to eat a large meal 2 h before testing and not to wear tight fitting clothing as under these circumstances results may be adversely be effected, interpreting results, and clinically significant change. The pulmonary function evaluation was performed using spirometry and followed the criteria established by the American Thoracic Society.

The following parameters were obtained as follows: forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), Tüffenau index (FEV1/%FVC), forced expiratory flow 25%–75% (FEF25%–75%), and peak expiratory flow (PEF). In the patient group, spiro-metry was carried out after HD. The time interval between the end of HD and the postdialysis study was within 12 h. Spirometry procedure was performed on each patient three times, and the best result was used. One trained technician led this procedure.

Laboratory procedures: (for both patients and controls)

Collection and processing of blood samples; routine laboratory investigations including: CBC, liver function test, kidney function test, CRP, and serum electrolytes including (Na, K, Ca, and Mg), on the same day of clinical assessments and doing PFTs. Blood samples (5 mL, in tubes-containing ethylenediaminete-traacetic acid or heparin for each participant) were collected postdialysis from arterial dialysis line from HD patients and from arterial puncture in healthy controls to measure ABG and NO levels.

All collected blood samples were centrifuged for 15 min at 1000 × g within 30 min of collection measuring blood levels of NO. Plasma samples were stored at <−20°C and analysis was performed by a biochemist. The kit used was the total NO and Nitrate/Nitrite assay kit. Arterial blood was analyzed for pH, PaO2, and PaCO2 with an instrumentation laboratory blood gas analyzer. Laboratory investigators were blind to the identity of the subject (patient vs. normal), which was indicated by a code number maintained by the clinical staff until all biochemical analyses were completed.

Statistical tests were performed using the Statistical Package for the Social Sciences (SPSS) software version 13.0 (SPSS Inc., Chicago, IL, USA). The paired t-test and the Pearson correlation coefficient test were used for comparisons before and after dialysis and testing the correlation between continuous variables, respectively. Values of P <0.05 were considered statistically significant.


   Results Top


There is no statistically significant difference between both groups regarding age and sex, but the values of height, weight, and body mass index (BMI) in the patient group, which were lower, were statistically highly significant in comparison to controls [Table 1].
Table 1: Sociodemographic characteristics and anthropometric parameters of cases and controls.

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There is no statistically significant difference between patients and controls in ABG values, but the difference was significant between patient and control groups regarding NO levels with higher levels in the case group. Furthermore, there was statistically significant difference between patient and control groups regarding all PFTs (except FEV1/FVC) with low performance in case group in both tests [Table 2].
Table 2: The difference in ABG, nitric oxide and pulmonary function tests characteristics between cases (before session) and controls.

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We also found that there is negative but not statistically significant correlation between the PFTs and ABG in case group and that there is statistically significant negative correlation between NO and some of the PFTs such as FEV1, FVC, PEF, and maximal mid-expiratory flow (MMEF), and there was negative correlation, but not statistically significant, between NO and the other pulmonary function tests, namely, MEF75-50 and MEF25 in the case group [Table 3]. The correlation between NO and FVC and FEV1 in case group is shown in [Figure 1].
Table 3: Correlation between pulmonary function tests and ABG in case group.

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Figure 1: Scatter chart with line for correlation between nitric oxide and FVC and FEV1 in the case group.
FVC: Forced vital capacity, FEV1: Forced expiratory volume in 1 s.


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[Table 4] shows the effect of dialysis on pulmonary functions tests and NO levels; only the FVC of patients significantly improved after the HD session. Other pulmonary function parameters, including VC, FEV1, and FEV1/ FVC ratio had no significant changes in comparison with those before HD.
Table 4: The difference in ABG, nitric oxide, and pulmonary function tests characteristics in cases before and after session.

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   Discussion Top


Pulmonary dysfunction may be the direct consequence of circulating uremic toxins or may result indirectly from volume overload, anemia, immune suppression, extraosseous calcification, malnutrition, electrolyte disorders, and/or acid−base imbalances.[5] Several studies revealed an increase in plasma concentration of NO in dialyzed patients both HD and peritoneal dialysis (CAPD) compared to healthy controls. However, the effects of NO on respiratory function in these patients are less known.[6] In addition to its powerful vasodila-tative effects, NO express bronchoconstrictive effects as well.[7]

In this study, we evaluated the pulmonary function and NO level among ERSD children treated with HD compared to healthy controls to show the correlation between NO levels and pulmonary function in these patients and in addition to evaluate the effect of dialysis on both pulmonary function and NO level. Regarding NO in ESRD patients and healthy controls there was significant elevation in patient than control group. This fact is supported by studies which showed that patients in terminal stages of uremia who are treated with regular HD had NO levels two to six times elevated compared to the healthy population.[8] Meenakshi and Agarwal[9] and Kovačević[6] also showed significantly higher serum levels of NO in patients treated with HD and CAPD compared to control group.

We found no significant difference between NO level before and after dialysis sessions. Similarly, Sarkar[10] found that there was no appreciable fall in the serum NO, despite the participants being on regular sessions of dialysis. NO and its metabolites are small diffusible molecules which should normally be easily eliminated by dialysis. It is therefore possible that there are other factors which contribute to the increased NO levels, which may be an increased endogenous production, the hyperactive L-arginine/ NO synthetic pathway and the activation of the immune system by the dialysis procedure itself, leading to the induction of iNOS and also the platelets which generate more NO due to uremia.[4] In contrast, Nagane found that mean values of NO were significantly decreased in post-HD samples as compared to pre-HD samples.[11]

Regarding ABG in ESRD patients and healthy controls, we found no statistically significant difference between patient and control groups in ABG. The results are in agreement with those of Herrero[12] who found that PaO2 and PaCO2 levels were similar and within the normal range in both HD group and control group.

In our study, there was the statistically significant difference between patient and control groups regarding all PFTs except FEV1/FVC. There is no statistically significant difference between patient and control groups. The results are in agreement with those of Kovacević et al[13] who found that patients who are on long-term HD show a significant decline in FVC. These results are also in agreement with those of Karacan et al[14] who reported forced expiratory flow between 25% and 75% of vital capacity was slightly below normal in the dialysis patients.

An interesting finding in our study was that we found a negative correlation between NO and some PFTs (FEV1, FVC, PEF, and MMFF) and there was negative correlation although not statistically significant between NO and the other PFTs (MEF75–50 and MEF25) in the case group. However, in the control group, there was no significant correlation between NO and any PFTs. The study results are in agreement with those of previous study[15] which found that spirometry parameters (percentages of predicted values) are significantly lower in patients with NO levels higher than 9.5 μmol/L compared to patients with NO levels lower than 9.5 μmol/L in both groups of tested patients. In dialyzed groups of patients, they found obstructive and restrictive (reduction of pulmonary volume) lung diseases. Results of other authors who studied spirometry parameters in different dialysis modules are scarce; hence, the comparison is difficult.

NO have proinflammatory effect, creating a vicious circle of pathophysiologic events. The cumulative effect to the bronchial tree can be seen as bronchoconstriction and accompanied by inflammation.[16] This fact is supported by studies which showed that patients in the terminal stage of uremia who are treated with regular HD had NO levels two to six times elevated compared to the healthy population.[8],[17] As an evidence of the effects of NO in the pathogenesis of pulmonary hypertension as well as its effects on respiratory function, results from some studies showed that 40% of patients treated with regular HD have pulmonary hypertension.[18]

This study suggests that levels of NO can be a marker of clinical deterioration rather than the cause of airway obstruction in patients who are in the terminal stage of renal insufficiency and who are treated with one or the other modes of dialysis.

The ABG parameters were also compared to NO level, and there was no apparent correlation between ABG parameters and plasma NO level. However, more studies with a larger sample size are required to evaluate this factor further. Furthermore, we could not find any published reports related to changes in ABG after HD and its correlation with blood levels of NO.

In this study, we also found that there was negative but no statistically significant correlation between duration of dialysis and PFTs in the patient's group. Several other studies also have found that there was insignificant, an inverse correlation between the duration of dialysis with FEV1, FVC, FEF 25%-75%, PEF and FEV1/FVC in the HD patients.[12],[19],[20]

We found that the effect of dialysis on pulmonary functions tests and NO levels; only the FVC of patients significantly improved comparing after the HD, this matched with Rahgoshai et al[2] and can be probable explanation for the improvement in FVC, but not in VC after HD is an improvement in small airway resistance after HD.


   Conclusion Top


We found that patients with ESRD on HD show lower values of lung function tests than those of the general population. However, postdialysis blood gases remained within normal reference levels. NO may be involved in the deterioration of pulmonary function and can be a marker of clinical deterioration; as the mean values of all spirometric parameters in patients with higher plasma NO level (after HD session) were lower than in patients with low plasma NO level. Thus, we hypothesize that endogenous NO may have a key role in many physiological and pathophysiological events in the lung; when produced in low concentrations, cNOS appears to have a generally beneficial role, but when produced in large amounts iNOS may result in increased inflammatory responses and tissue damage.


   Limitation of the study Top


This being a cross-sectional, rather than the longitudinal design of our study, we cannot support a definitive causal relationship. Longitudinal studies directly addressing the possible role that NO may play a role in decreased pulmonary function in ESRD under HD. Hence, different designs of other studies, differences in sample sizes, differences in techniques of measuring NO levels, differences in stages of illness progression and different illness courses may play a role in this variability of results.

Conflict of interest: None declared.

 
   References Top

1.
Pierson DJ. Respiratory considerations in the patient with renal failure. Respir Care 2006; 51:413-22.  Back to cited text no. 1
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Rahgoshai R, Rahgoshai R, Khosraviani A, Nasiri AA, Solouki M. Acute effects of hemo-dialysis on pulmonary function in patients with end-stage renal disease. Iran J Kidney Dis 2010;4:214-7.  Back to cited text no. 2
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Bredt DS, Hwang PM, Snyder SH. Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 1990;347: 768-70.  Back to cited text no. 3
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Brunini TM, Mendes-Ribeiro AC, Ellory JC, Mann GE. Platelet nitric oxide synthesis in uremia and malnutrition: A role for L-Arginine supplementation in vascular protection? Cardiovasc Res 2007;73:359-67.  Back to cited text no. 4
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Senatore M, Buemi M, Di Somma A, Sapio C, Gallo GC. Respiratory function abnormalities in uremic patients. G Ital Nefrol 2004;21:29-33.  Back to cited text no. 5
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Kovačević P, Dragić S, Rajkovača Z, Veljković S, Kovačević T. Effects of different dialyzed models on serum levels of nitric oxide and endothelin-1 in patients with end stage renal disease. Austin Ther 2014;1:4.  Back to cited text no. 6
    
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Terada A, Fujisawa T, Togashi K, et al. Exhaled nitric oxide decreases during exercise-induced bronchoconstriction in children with asthma. Am J Respir Crit Care Med 2001;164:1879-84.  Back to cited text no. 7
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Schmidt RJ, Baylis C. Total nitric oxide production is low in patients with chronic renal disease. Kidney Int 2000;58:1261-6.  Back to cited text no. 8
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Meenakshi SR, Agarwal R. Nitric oxide levels in patients with chronic renal disease. J Clin Diagn Res 2013;7:1288-90.  Back to cited text no. 9
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Sarkar SR, Kaitwatcharachai C, Levin NW. Nitric oxide and hemodialysis. Semin Dial 2004;17:224-8.  Back to cited text no. 10
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Nagane NS, Ganu JV, Jagtap PE. Study of oxidative stress in pre - and post-hemodialysis in chronic renal failure patients. Biomed Res 2013;24:498-502.  Back to cited text no. 11
    
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Herrero JA, Alvarez-Sala JL, Coronel F, et al. Pulmonary diffusing capacity in chronic dialysis patients. Respir Med 2002;96:487-92.  Back to cited text no. 12
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Kovacević P, Stanetic M, Rajkovaca Z, Meyer FJ, Vukoja M. Changes in spirometry over time in uremic patients receiving long-term hemodialysis therapy. Pneumologia 2011;60: 36-9.  Back to cited text no. 13
    
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Karacan O, Tutal E, Colak T, et al. Pulmonary function in renal transplant recipients and end-stage renal disease patients undergoing maintenance dialysis. Transplant Proc 2006;38:396-400.  Back to cited text no. 14
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Pedja K, Sasa D, Raj Z, Tijana K. The correlation between nitric oxide levels and spiro-metry in dialyzed patients compared to healthy subjects. Enliven Nephrol Renal Stud 2014; 1:002.  Back to cited text no. 15
    
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Yang X, Sun Q, Asim MB, et al. Nitric oxide in both bronchoalveolar lavage fluid and serum is associated with pathogenesis and severity of antigen-induced pulmonary inflammation in rats. J Asthma 2010;47:135-44.  Back to cited text no. 16
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Schmidt RJ, Domico J, Samsell LS, et al. Indices of activity of the nitric oxide system in hemodialysis patients. Am J Kidney Dis 1999;34:228-34.  Back to cited text no. 17
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Yigla M, Keidar Z, Safadi I, et al. Pulmonary calcification in hemodialysis patients: Correlation with pulmonary artery pressure values. Kidney Int 2004;66:806-10.  Back to cited text no. 18
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Rezaeetalab F, Zeraati A, Fadaeian AM, et al. Spirometric parameters: Hemodialysis compared to peritoneal dialysis. J Cardiothorac Med 2015;3:293-6.  Back to cited text no. 19
    
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Correspondence Address:
Dr. Doaa Mohammed Youssef
Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-2442.235174

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