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ORIGINAL ARTICLE
Year : 2019  |  Volume : 12  |  Issue : 6  |  Page : 511-515  

Blood pressure trends in idiopathic steroid-sensitive childhood nephrotic syndrome: A prospective observational study


1 Department of Pediatrics, NRS Medical College, Kolkata, West Bengal, India
2 Department of Pediatrics, Asansol District Hospital, Asansol, West Bengal, India
3 Department of Pediatrics, IPGMER, Kolkata, West Bengal, India

Date of Submission31-Dec-2018
Date of Acceptance29-Mar-2019
Date of Web Publication17-Oct-2019

Correspondence Address:
Madhumita Nandi
6/6, Naren Sarkar Road, Kolkata - 700 008, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjdrdypu.mjdrdypu_262_18

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  Abstract 


Background: It has been observed that blood pressure (BP) tends to rise in children with idiopathic nephrotic syndrome (NS) in the acute stage, during attack or relapse, and may reverse back to normal with time. However, there is a lacuna of knowledge regarding the actual trend of BP in these children when they are in medication-free period. The study was conducted to analyze the trend of BP in these children as persistent hypertension (HTN) is an important determinant of future cardiovascular morbidity. Materials and Methods: This was a prospective observational study over 6-month duration in children with diagnosis of idiopathic childhood NS wherein BP recordings were followed up and HTN was managed with medications if required. The secondary causes of HTN and steroid-resistant, steroid-dependent, and frequently relapsing NS were excluded. Results: At initial presentation, 36.4% of children had elevated BP of which 9.0% needed antihypertensive drugs. The corresponding values at remission were 66.6% and 15.15% with a declining trend seen in follow-up. Antihypertensive medications had to be given to 22 (33.33%) children for a mean duration of 30.5 ± 21.8 (range: 7–105) days. There was a significant relation between nadir of serum albumin at the time of attack and number of days to go into remission with incidence of HTN (<0.05). Conclusions: Meticulous tracking of BP is essential in children with idiopathic NS as elevated BP, although to a milder degree, is noted in a significant percentage of these children.

Keywords: Blood pressure, nephrotic syndrome, trend


How to cite this article:
Samanta M, Nandi M, Bhattacharya S, Naskar A, Das MK. Blood pressure trends in idiopathic steroid-sensitive childhood nephrotic syndrome: A prospective observational study. Med J DY Patil Vidyapeeth 2019;12:511-5

How to cite this URL:
Samanta M, Nandi M, Bhattacharya S, Naskar A, Das MK. Blood pressure trends in idiopathic steroid-sensitive childhood nephrotic syndrome: A prospective observational study. Med J DY Patil Vidyapeeth [serial online] 2019 [cited 2019 Nov 19];12:511-5. Available from: http://www.mjdrdypv.org/text.asp?2019/12/6/511/269432




  Introduction Top


Idiopathic primary nephrotic syndrome (NS) is a common condition in children. Most of these patients are steroid responders in whom the disease follows a benign course ultimately going into drug-free long-term remission after varying number of relapses.[1],[2] Some of these children have their blood pressure (BP) elevated to varying degrees in the acute stage, during attack or relapse. Various factors have been implicated for this elevation,[3],[4] which are expected to reverse back to normal physiology once remission is achieved, bringing BP value to normal level. However, there is indeed a lacuna of knowledge regarding the trend of BP in these children when they are in medication-free remission for long periods of time. Published literature on this issue, although scanty, have all indicated persistence in hypertension (HTN) in at least some of these children.[5],[6],[7],[8],[9],[10],[11],[12] As persistent HTN is an important determinant of future cardiovascular morbidity and mortality, it is important to assess the degree and duration of this raised BP if at all requiring antihypertensive drugs.


  Materials and Methods Top


We aimed to delineate the incidence of high BP in childhood idiopathic NS and to find how it tracks at 3-month and 6-month medication-free postremission in a prospective observational study. After approval from the Institutional Ethics Committee and written informed consent, children from 1 to 12 years of age with a diagnosis of idiopathic NS either for the first time or presenting with relapse after maintaining remission and remaining medication free for least 3 months were included in the study. NS was diagnosed according to the guidelines of the Indian Pediatric Nephrology Group.[1],[2]

The BP of the right arm was recorded with a sphygmomanometer with appropriate size cuffs in sitting posture thrice at a gap of 5–10 min, and the mean BP was noted.[13],[14] The reading was plotted in an appropriate chart and categorized as per the Fourth US Task Force Report on Hypertension into pre-HTN (90th–95th percentile), HTN Stage I (95th–99th +5 mmHg), and HTN Stage II (>99th +5 mmHg), respectively.[13] If systolic BP and diastolic BP were different, the one with higher percentile was used for defining and staging HTN.[14] Children having BP between 90th and 95th percentiles were given salt-restricted diet and advised lifestyle modifications only. Antihypertensive drugs were given when BP was >95th percentile and withdrawn when it came down to <95th percentile. Angiotensin-converting enzyme inhibitors were used as first-line agents for the management of HTN. Other agents if needed were diuretics and calcium channel blockers. Supportive and definitive management of NS was given as per the ISPN guidelines.[1],[2]

The details of the children were entered in a predesigned pro forma which contained information about their demographic profile, clinical course during the acute phase/relapse, and BP records on presentation, on remission, on withdrawal of steroids, at 3 months of drug-free remission, and at 6 months of drug-free remission, wherever possible.

Children with gross hematuria or renal insufficiency or systemic diseases such as rash, fever, joint symptoms, and organomegaly or having a family history of essential HTN or whose parents had BP >130/90 mmHg as measured by the authors or who relapsed within 3 months of achieving remission and so could not be medication free for at least 3 months or whose body mass index (BMI) was >95th percentile were excluded from the study. Children with underlying structural kidney abnormalities were also excluded. During the course of treatment, children who did not respond to standard dose of prednisolone for 4 weeks and thus declared steroid resistant were also excluded from final consideration. Furthermore, children with a history of steroid dependence or resistance were also excluded. Children who gained weight during the study period to a BMI > 95th percentile were excluded.

The data were entered into MS Excel and then analyzed with STATISTICA version 8 (Tulsa, Oklahoma, USA: StatSoft Inc; 2007) and MedCalc version 11.6 (Mariakerke, Belgium: MedCalc Software bvba; 2011) statistical software. Nonparametric values were expressed in terms of percentage with 95% confidence interval (95% CI) values. Parametric values were expressed in terms of mean ± standard deviation (SD). Paired t-test was used for comparison of parametric variables. P < 0.05 was taken to be statistically significant. Pearson correlation (r) was used to compare the variables with incidence of elevated BP.


  Results and Analysis Top


Of 89 children who were considered initially, 66 were followed up and analyzed according to the predesigned protocol excluding the rest based on the specified exclusion criteria [Figure 1]. The mean age (± SD) at inclusion in the study was 5.86 ± 2.99 years (range: 3–8 years) with male: female ratio being 1.4:1. The mean age of onset of the disease was 4.17 ± 2.02 years (range: 3–5 years). Thirty-three children were diagnosed as NS for the first time. The mean (± SD) number of relapses of NS was 3.23 ± 3.32. The maximum number of relapses was 15 in a 12-year-old boy whose disease had begun at the age of 4 years. The mean (± SD) days to remission were 11.79 ± 4.21. Four (6.06%) children needed albumin infusion for control of edema, the rest responding only to steroids.
Figure 1: Patient flow

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Twenty-four (36.4%) children had elevated BP or HTN at presentation of which 6 (9.0%) needed treatment with antihypertensive drugs. By the time of remission, 44 (66.6%) had HTN of which 10 (15.15%) needed antihypertensive drugs [Figure 2]. At the time of steroid withdrawal (daily plus alternate day), the BP was high in 36 (54.55%) children, 13 requiring drugs. At 3 months, of 59 children, 18 (27.27%) had high BP, none requiring drugs. At 6 months, of 49 children, 10 (15.15%) had BP in prehypertensive range, thus none requiring antihypertensive medication. Antihypertensive medications had to be given to 22 (33.33%) children for a mean duration of 30.5 ± 21.8 (range: 7–105) days.
Figure 2: Line chart showing children with elevated blood pressure at presentation and at different stages of follow-up

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While attempting to delineate the correlation of incidence of HTN with various other clinical parameters [Table 1], it was found that there was a significant relation between nadir of serum albumin at the time of attack with incidence of HTN throughout the study period starting from BP at presentation to BP at 6-month follow-up (P = 0.000–0.060). Although the incidence of high BP throughout the study period was found to be more in those who needed albumin infusion, this correlation was statistically significant only at presentation (P = 0.004, r = 0.35) and 3 months (P = 0.046, r = 0.27). BP significantly correlated with the number of days the children took to go into remission [Table 1]. Throughout the 6-month period, the children who had HTN had taken significantly more number of days to remit. The incidence of HTN did not vary with age of onset or age of presentation of disease or the total number of attacks for each child. Although the number of relapses was not statistically significantly different in the two groups at 3- and 6-month follow-up, it was higher in those with elevated BP and that could reflect more steroid exposure. As we could not compare BP with cumulative dose of steroids because of lack of availability of meticulous retrospective data, the number of previous attacks was taken as an indirect representation for this association as children with more number of attacks are expected to have been exposed to more cumulative dose of steroids.
Table 1: Correlation of elevated blood pressure with clinical factors at presentation

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  Discussion Top


Different studies have reported a varied incidence of HTN in idiopathic NS in children ranging from 10% to 30%.[15],[16],[17] We found an incidence of 36.3% although most of them had elevation in the range of 90th–95th percentile. Only 9% had BP elevated to more than 95th percentile in the acute stage at presentation requiring antihypertensive medication. Various factors contribute to elevated BP in acute stage such as intense vasoconstriction, hyperlipidemia, and steroid therapy and certain physiological changes in glomerular filtration dynamics due to the disease process itself like activation of renin–angiotensin–aldosterone system (RAAS).[3],[4] In addition, Kleyman did describe how plasminogen that appears in the filtrate gets converted to plasmin in the tubules and activates the epithelial sodium channel. This increases the absorption of filtered sodium from tubules leading to elevated BP. Moreover, atrial natriuretic peptide signaling appears to be blunted in some individuals with NS.[1],[2]

It is expected that the BP normalizes once remission is achieved and steroid therapy is withdrawn. There is really a dearth of published literature on follow-up BP in these children after remission is achieved, to see how far this holds true. The follow-up studies published on childhood NS have been mostly on the disease behavior, impact on growth, bone density, cataract, kidney functional status, etc., on long term,[5],[6],[7],[8],[9],[10],[11],[12] but only a few have specifically focused on meticulous BP follow-up of these children. A study on adult patients by Vivante et al. found HTN in 13.6% of men with a history of glomerular disease in childhood as compared to 7.4% in those without any such history in childhood.[11] Kyrieleis et al. reported high BP needing medications in 6 of 15 patients of childhood frequently relapsing NS after a median follow-up of 24 years. However, as all the patients were frequently relapsing, they needed long-term continuous steroids and other medications.[8] A study from China reported HTN in 8.6% of children with NS on long-term follow-up but again that included patients who behaved as frequent relapse, steroid dependent, and steroid resistant.[12] One would be interested in knowing the BP outcome of those children who do not suffer from frequent relapses and are thus disease free and drug free for varying periods of time.

Throughout the study period, we found a significant correlation between HTN with the nadir of serum albumin and the number of days to remission. However, even after extensive search, we could not find any previously published literature highlighting this correlation. We hypothesize that it could probably be that lower levels of albumin activate the RAAS to a higher degree resulting in more vasoconstriction and fluid retention with a consequent higher BP, the effect of which probably persists to some extent even after remission. Longer days to remit and HTN could also be explained due to the same fact.

We observed that proportionately more children had elevated BP at remission and at the time of steroid withdrawal as compared to that at presentation which could be due to the effect of steroid therapy itself. Although in most of these children, BP was normalized at 3 and 6 months of drug- and disease-free period, in some of them, the BP persistently remained elevated in pre-HTN range.

Although none of the children at 6 months had HTN in the range to need antihypertensive medication, a significant percentage of them (around 20%) had high BP albeit in the pre-HTN range even while off steroids for >6 months. These children obviously need more meticulous tracking and follow-up to see it persists or not. As HTN is one of the important determinants of future lifestyle disorders and organ damage, it is important that all children with HTN even in idiopathic primary NS undergo long-term BP monitoring.

Limitations

Our study depicts the trend of BP in idiopathic childhood NS. However, it has its' share of limitations. This was a single-center study with a follow-up of only 6 months of steroid-free period. A multicentric long-term study can give us the true implications of elevated BP in idiopathic NS as regards its persistence long after they become “disease free” and “steroid free” and if this elevation might track even to adulthood. We have not been able to study relation between BP and hyperlipidemia as serum lipid levels in relapse cases were not available as it is not done on a routine basis. As none of our patients had significantly elevated BP on persistent basis, none of them underwent biopsy. Hence, the exact histopathological subset categorization of our study population is not known. Moreover, the response to steroid therapy carries a greater prognostic weight than the histologic features seen on initial renal biopsy.[18] Furthermore, the study was conceived and started based on the Fourth US Task Force Report on Hypertension.[13],[14] However, when the study was halfway through the 2017 guidelines on hypertension[19] were published, where there is a change in the categorization of HTN. As the study was already going on, it was not possible to incorporate these changes.


  Conclusions Top


This study does give an insight on the need for meticulous tracking of BP even in children with idiopathic NS as high BP is noted in a significant percentage of children during attack/relapse of idiopathic NS and up to 6 months of remission. Associated factors in acute stage significantly correlating with elevated BP are lower serum albumin, need for albumin infusion, and the number of days taken for remission. Larger studies of longer duration could delineate if this elevation persists in future into adulthood with implications on cardiovascular mortality and morbidity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Srivastava RN, Bagga A, editors. Nephrotic syndrome. In: Pediatric Nephrology. 4th ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2005. p. 159-200.  Back to cited text no. 1
    
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Indian Pediatric Nephrology Group; Indian Academy of Pediatrics, Bagga A, Ali U, Banerjee S, Kanitkar M, Phadke KD. Management of steroid sensitive nephrotic syndrome: Revised guidelines. Indian Pediatr 2008;45:203-14.  Back to cited text no. 2
    
3.
Kleyman TR, Hughey RP. Plasmin and sodium retention in nephrotic syndrome. J Am Soc Nephrol 2009;20:233-4.  Back to cited text no. 3
    
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Ray EC, Rondon-Berrios H, Boyd CR, Kleyman TR. Sodium retention and volume expansion in nephrotic syndrome: Implications for hypertension. Adv Chronic Kidney Dis 2015;22:179-84.  Back to cited text no. 4
    
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Hacıhamdioǧlu DÖ, Kalman S, Gök F. Long-term results of children diagnosed with idiopathic nephrotic syndrome; single center experience. Turk Pediatri Ars 2015;50:37-44.  Back to cited text no. 5
    
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Hjorten R, Anwar Z, Reidy KJ. Long-term outcomes of childhood onset nephrotic syndrome. Front Pediatr 2016;4:53.  Back to cited text no. 6
    
7.
Ishikura K, Yoshikawa N, Nakazato H, Sasaki S, Nakanishi K, Matsuyama T, et al. Morbidity in children with frequently relapsing nephrosis: 10-year follow-up of a randomized controlled trial. Pediatr Nephrol 2015;30:459-68.  Back to cited text no. 7
    
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Kyrieleis HA, Löwik MM, Pronk I, Cruysberg HR, Kremer JA, Oyen WJ, et al. Long-term outcome of biopsy-proven, frequently relapsing minimal-change nephrotic syndrome in children. Clin J Am Soc Nephrol 2009;4:1593-600.  Back to cited text no. 8
    
9.
Fakhouri F, Bocquet N, Taupin P, Presne C, Gagnadoux MF, Landais P, et al. Steroid-sensitive nephrotic syndrome: From childhood to adulthood. Am J Kidney Dis 2003;41:550-7.  Back to cited text no. 9
    
10.
Rüth EM, Kemper MJ, Leumann EP, Laube GF, Neuhaus TJ. Children with steroid-sensitive nephrotic syndrome come of age: Long-term outcome. J Pediatr 2005;147:202-7.  Back to cited text no. 10
    
11.
Vivante A, Twig G, Tirosh A, Skorecki K, Calderon-Margalit R. Childhood history of resolved glomerular disease and risk of hypertension during adulthood. JAMA 2014;311:1155-7.  Back to cited text no. 11
    
12.
Kwong VW, Kwan BC, Chow KM, Leung CB, Li PK, Szeto CC. Long-term outcome of biopsy-proven minimal-change nephrotic syndrome in Chinese children. Hong Kong J Nephrol 2013;15:22-7.  Back to cited text no. 12
    
13.
National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004;114:555-76.  Back to cited text no. 13
    
14.
Bagga A, Jain R, Vijayakumar M, Kanitkar M, Ali U. Evaluation and management of hypertension. Indian Pediatr 2007;44:103-21.  Back to cited text no. 14
    
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Sahana KS. Clinical profile of nephrotic syndrome in children. J Evol Med Dent Sci 2014;3:863-70.  Back to cited text no. 15
    
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White RH, Glasgow EF, Mills RJ. Clinicopathological study of nephrotic syndrome in childhood. Lancet 1970;1:1353-9.  Back to cited text no. 16
    
17.
Safaei A, Maleknejad S. Spectrum of childhood nephrotic syndrome in Iran: A single center study. Indian J Nephrol 2009;19:87-90.  Back to cited text no. 17
[PUBMED]  [Full text]  
18.
Niaudet P. Long-term outcome of children with steroid-sensitive idiopathic nephrotic syndrome. Clin J Am Soc Nephrol 2009;4:1547-8.  Back to cited text no. 18
    
19.
Flynn JT, Kaelber DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics 2017;140. e20171904.  Back to cited text no. 19
    


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