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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 4-9

Endothelial dysfunction in children with frequently relapsing and steroid-resistant nephrotic syndrome


1 Department of Pediatrics, Division of Pediatric Nephrology, Postgraduate Institute of Medical Education and Research and Associated Dr. Ram Manohar Lohia Hospital, New Delhi, India
2 Division of Pediatric Nephrology, Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children Hospital, New Delhi, India
3 Department of Biochemistry, Postgraduate Institute of Medical Education and Research and Associated Dr Ram Manohar Lohia Hospital, New Delhi, India
4 Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India

Date of Submission27-Nov-2019
Date of Decision14-Feb-2020
Date of Acceptance31-Mar-2020
Date of Web Publication27-Jun-2020

Correspondence Address:
Abhijeet Saha
Department of Pediatrics, Division of Pediatric Nephrology, Lady Hardinge Medical College and Kalawati Saran Children Hospital, New Delhi - 110001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJPN.AJPN_28_19

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  Abstract 


Background: Impaired endothelial function is a precursor of the atherosclerotic process leading to cardiovascular adverse events. This study evaluated endothelial dysfunction using endothelial markers in children with steroid-resistant NS (SRNS) and frequently relapsing or steroid-dependent NS (FRNS/SDNS). Methods: This was a cross-sectional study with short-term follow up. Thirty-five patients with nephrotic syndrome (NS), aged 1–18 years, including 19 with frequent relapses or steroid-dependent NS (FRNS/SDNS) and 16 with steroid resistant NS (SRNS), and 19 age- and gender-matched controls, were enrolled for the study. Soluble thrombomodulin (sTM), plasminogen activator inhibitor 1 (PAI-1), and von Willebrand factor (vWF) levels were measured in patients with FRNS/SDNS in relapse and after 6 months of steroid-induced remission, at diagnosis in SRNS, and in controls. Results: Levels of vWF, PAI-1, and sTM were significantly higher than controls in patients with active NS (FRNS/SDNS in relapse or SRNS; P < 0.0001). Patients with FRNS/SDNS had significantly elevated vWF levels, compared to controls, even after 6 months of corticosteroid therapy. Levels of vWF were significantly higher for patients with recently diagnosed SRNS than relapse of FRNS/SDNS (P < 0.0001). Conclusion: Children with FRNS/SDNS and SRNS have significant endothelial dysfunction in all stages of disease in varying severity. It is unclear whether persistently elevated biomarkers of endothelial dysfunction contribute to future atherosclerotic events in patients with NS.

Keywords: Atherosclerosis, cardiovascular morbidity, minimal change disease


How to cite this article:
Bhatia A, Saha A, Deepthi B, Goyal P, Upadhyay AD, Dubey NK. Endothelial dysfunction in children with frequently relapsing and steroid-resistant nephrotic syndrome. Asian J Pediatr Nephrol 2020;3:4-9

How to cite this URL:
Bhatia A, Saha A, Deepthi B, Goyal P, Upadhyay AD, Dubey NK. Endothelial dysfunction in children with frequently relapsing and steroid-resistant nephrotic syndrome. Asian J Pediatr Nephrol [serial online] 2020 [cited 2020 Oct 28];3:4-9. Available from: https://www.ajpn-online.org/text.asp?2020/3/1/4/288151




  Introduction Top


Recent literature suggests that children with idiopathic nephrotic syndrome (NS) are predisposed to endothelial dysfunction, leading to atherosclerotic changes, and even acute myocardial infarction.[1],[2],[3],[4],[5],[6] While altered lipid metabolism is an established modifiable risk factor for atherosclerosis and cardiovascular health in adults, analogous cardiovascular risk factors in children with NS are still being studied.[6],[7],[8] The characterization of endothelial dysfunction using biomarkers might help in early identification of early premature onset atherosclerosis and subclinical cardiovascular morbidity.

Impaired endothelial function might evolve into symptomatic atherosclerosis, and hence indirectly indicates risk of future cardiovascular events.[9],[10] Exposure to proatherogenic risk factors leads to endothelial activation and injury, leading to release of circulatory markers from activated or apoptotic endothelial cells.[11],[12],[13] Von Willebrand factor (vWF), released in response to endothelial damage, is a multimeric glycoprotein that serves as a carrier to factor VIII and helps mediate intimal platelet adhesion through the glycoprotein Ib-IX complex.[12],[13],[14] The soluble form of thrombomodulin (sTM) or CD141, cleaved from the transmembrane form following endothelial injury during inflammation, promotes thrombin-mediated protein C activation.[15],[16] Plasminogen activator inhibitr-1 (PAI-1), a single-chain glycoprotein, is the principal inhibitor of the activators of plasminogen, and hence fibrinolysis, and is released soon after endothelial damage.[17] Hence, all three substances appear to be valid markers of endothelial injury. We have previously reported their levels at onset of NS.[18] Since there is a paucity of literature on endothelial injury in patients with steroid-resistant NS (SRNS) and frequently relapsing or steroid-dependent NS (FRNS/SDNS), the present study was planned to compare the plasma levels of vWF, PAI-1, and sTM in these patients with those in healthy children.


  Methods Top


Study design and participants

This cross-sectional study, with short-term follow-up, was performed over 16 months, from November 2013 to March 2015 at a tertiary care hospital in New Delhi, India. Following approval by the Institutional Ethics Committee (1-40/65/2013/IEC/Thesis/PGIMER-RMLH/0318) and informed parental consent, patients between 1 and 18 years of age and diagnosed with FRNS (≥2 relapses within 6 months of initial response or >4 relapses in any year), SDNS (two consecutive relapses when on alternate day prednisolone, or within 14 days of its discontinuation), and SRNS (persistent proteinuria despite daily prednisolone therapy at a dose of 2 mg/kg/day for 4 weeks, after ensuring lack of infection or nonadherence to medication) were enrolled. Exclusion criteria included secondary NS, venous thromboembolism, preexisting hypertension, diabetes mellitus, recent transfusion of blood product, therapy with drugs affecting endothelial function, and refusal of consent. We also included healthy, age- and sex-matched controls. Patients with FRNS/SDNS were sampled twice, at diagnosis and 6 months later. At enrollment and during follow-up, these patients were only on corticosteroids and did not receive a second-line therapeutic agent. Patients with SRNS were sampled once at diagnosis and underwent ultrasound-guided percutaneous renal biopsy to confirm histology.

Laboratory methods

The primary outcome measure was levels of sTM, PAI-1, and vWF at diagnosis of FRNS/SDNS, as compared to after 6 months of steroid-induced remission, at diagnosis of SRNS and in controls. Blood samples were centrifuged at 2800 G for 10 min to derive plasma, which was immediately stored in four aliquots at −70°C until assays. Endothelial markers were quantitatively estimated using commercially available solid-phase sandwich enzyme-linked immunosorbent assay (ELISA) kits. The Gen-Probe (Diaclone SAS, Besancon Cedex, France) kit was used for estimating sTM, while the AssayMax Human ELISA kits (St. Charles, MO, USA) were used to detect PAI-1 and vWF. All measurements were done using Evolis Twin Plus instrument (Bio-Rad™). The intra-assay and inter-assay coefficients of variations were 4.9% and 7.1%, respectively, for vWF, 3.9% and 9.8%, respectively, for sTM, and 4.7% and 7.2%, respectively, for PAI-1.

Sample size calculation

Using reference values for mean ± standard deviation (SD) for sTM, tPA, and vWF levels from previous studies, for power of 80%, and alpha error of 5%, sample size was estimated at 20, 8, and 4 patients, respectively. In children with SRNS, using reference mean ± SD, power of 90%, and alpha error of 5%, the sample size was estimated at 10, 10, and 4 patients for sTM, tPA, and vWF, respectively.

Statistical analysis

Analysis was performed using SPSS (SPSS Inc., version 16.0, 2007; Chicago, USA). Continuous variables are presented as mean ± SD or median (interquartile range) depending on the normality of distribution, tested using the Kolmogorov–Smirnov test. Categorical variables were presented as frequency (percentage). Continuous data were compared among groups using one-way analysis of variance or Kruskall–Wallis test, as appropriate, and between paired and matched samples using the Wilcoxon signed-rank sum test. P < 0.05 was considered statistically significant.


  Results Top


We enrolled 35 patients with NS, including 19 patients with FRNS/SDNS at diagnosis, and 16 patients at diagnosis of SRNS, along with 19 controls. [Table 1] shows the baseline characteristics of the cases and controls. All children with FRNS/SDNS were in relapse with a spot urine protein-to-creatinine ratio (Up: Uc) of 5.9 (3.9, 8.6) mg/mg creatinine at diagnosis, and in remission after 6 months of steroid therapy. Patients with SRNS had Up: Uc of 5.5 (3.1, 10.8) at diagnosis. Height and body mass index (BMI) differed significantly between cases and controls, and BMI SDS did not differ from baseline to 6 months later among children with FRNS/SDNS (P = 0.80). Children with FRNS/SDNS and SRNS had high serum cholesterol, Up: Uc, and low albumin (P < 0.05) at diagnosis. Serum cholesterol and triglyceride levels in FRNS/SDNS declined from 406 (359,444) mg/dl and 343 (280,430) mg/dl, respectively, at diagnosis, to 198 (189.5, 238) mg/dl and 189 (167.5, 206.5) mg/dl at 6-month follow-up (in remission). Serum cholesterol and triglyceride levels in children with SRNS were 360.5 (260, 463.2) mg/sdl and 242 (174.5, 323) mg/dl, respectively.
Table 1: Baseline characteristics of patients and controls

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Levels of endothelial biomarkers

The levels of vWF, sTM, and PAI-1 were significantly higher in patients with FRNS/SDNS and SRNS at diagnosis, as compared to controls [Table 2]. The levels of sTM and PAI-1 fell significantly after 6 months of corticosteroid therapy in patients with FRNS/SDNS [Table 3]. However, levels of vWF did not differ significantly between the two time points [Table 3]. Levels of vWF, but not sTM or PAI-1, were significantly higher at onset of SRNS as compared with children with FRNS/SDNS at onset.
Table 2: Levels of markers of endothelial dysfunction at enrollment in patients and controls

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Table 3: Plasma levels of markers of endothelial dysfunction in frequently relapsing nephrotic syndrome

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Association of endothelial markers to biochemical characteristics

Total cholesterol was correlated positively to PAI-1 (r = 0.643; P < 0.001), sTM (r = 0.531; P < 0.001), vWF (r = 0.265; P = 0.027), and Up: Uc (r = 0.577; P < 0.001) and negatively with serum albumin (r = −0.603; P < 0.001). Multiple regression analysis, using levels of PAI-1, sTM, vWF, spot Up: Uc, and serum albumin, to predict serum total cholesterol levels, indicated that the model explained 62% of the variance, and was a significant predictor of hypercholesterolemia (F (3, 50) =27.34; P < 0.001). Levels of sTM (β = 2.624; P < 0.001), Up: Uc (β = 7.629; P = 0.004), and serum albumin (β = −63.45;β < 0.001) contributed significantly to the model.


  Discussion Top


Endothelial dysfunction is deemed as the “risk of the risk factors.”[19] Specific atherogenic risk factors in patients of NS might result in endothelial dysfunction, which is associated with future cardiovascular events. Endothelial markers are released secondary to endothelial injury; hence, their increased levels are consistent with endothelial dysfunction.[20] Our study revealed that levels of vWF, sTM, and PAI-1 were significantly increased in patients with FRNS/SDNS and SRNS at diagnosis [Table 2]. Despite remission of disease, some endothelial markers continued to be high, indicating persistent risk of atherosclerosis.

Sharma et al. and Tkaczyk, et al. observed that the levels of vWF, sTM, and PAI-1 were elevated in patients with first episode of NS [18],[20] and that endothelial dysfunction was most pronounced in relapse. Arumugam et al. demonstrated increased plasma levels of endothelin-1 at onset of NS, indicating a proinflammatory and prothrombotic state of the endothelium.[20],[21] Endothelial dysfunction was demonstrated in FSGS patients by increased levels of endothelial markers, including vWF, circulating endothelial cells (CECs), soluble vascular cell adhesion molecule-1 (sVCAM-1), sTM, and soluble e-selectin. Patients with thromboembolism had raised levels of CECs and vWF than those without thromboembolism.[22] Zhang et al. reported increased levels of vWF and sTM and Malyszko et al. found higher levels of sTM in NS cases as compared to controls.[22],[23] Therefore, overwhelming evidence supports the role of endothelial dysfunction even at the onset of NS. However, previous studies have not examined endothelial dysfunction in children with FRNS/SDNS.

Previous reports of endothelial injury at onset of NS improved during remission.[20],[24] Our study showed that the markers of endothelial dysfunction were significantly elevated in patients with FRNS/SDNS at diagnosis and the levels declined with remission, except vWF which continued to be elevated at 6 months of steroid therapy. This suggests that some amount of endothelial damage persists even at remission. As vWF is deemed a marker of endothelial activation, its persistent high levels indicate a chronic activation of the endothelium in patients with FRNS/SDNS.[25] Plausible mechanisms for its elevation in patients with FRNS/SDNS and SRNS are unremitting proteinuria, chronic exposure to steroids, and persistent hypoalbuminemia. These results are consistent with observations by Tkaczyk et al., who found that the endothelial markers sTM and PAI-1 decreased gradually over several months, but vWF activity increased in patients with NS, regardless of disease stage.[20] Sharma et al. illustrated that the levels of endothelial dysfunction markers fall after 12 weeks of remission of first episode of NS.[18] Zhang et al. showed that adults with FSGS have high levels of CECs, vascular cell adhesion molecule (VCAM-1), and sTM, that decline significantly after nonsteroidal immunosuppressive therapy, but vWF and sVCAM-1 persisted at high levels for a year despite complete remission.[22] In our study, we found significantly higher levels of vWF, sTM, and PAI-1 in patients with SRNS as compared to controls, and significantly elevated levels of vWF in patients with SRNS as compared to those with FRNS/SDNS, indicating an increased risk of endothelial injury in patients with steroid resistance as compared to steroid sensitive NS, suggesting a higher risk of accelerated atherosclerosis and perfusion abnormalities. Findings of the present work are consistent with our previous study, which found that the levels of tPA, vWF, and sTM were significantly raised in patients with SRNS compared to infrequently relapsing steroid sensitive NS.[18]

Hypercholesterolemia and hypoalbuminemia are reported to be associated with endothelial injury, and the present study suggests similar correlations. Previous studies in patients at onset of steroid sensitive NS and adults with FSGS suggest similar correlation.[18],[20] Some other published studies, however, show inconsistent relationships between these markers and biochemical parameters in NS.[20],[23]

Other endothelial markers that have been studied in NS recently include endothelin-1, asymmetric dimethylarginine, CECs, soluble e-selectin, VCAM, thrombomodulin, CD146, syndecan-1, intercellular adhesion molecule-1, and free homocysteine.[21],[22],[26],[27],[28],[29] Increasingly, reports emphasize the role of studying carotid intima-media thickness (cIMT) as a predictor of atherosclerosis.[30],[31],[32] A systematic review indicated an association between cIMT and coronary atherosclerosis or cardiovascular events.[33],[34] Flow-mediated dilatation (FMD) is another surrogate of endothelial function.[35] Overall, endothelial dysfunction has emerged as a critical concept and is understood as progressing continuously from reversible (Type I and II endothelial activation) to irreversible (endothelial apoptosis and necrosis) endothelial dysfunction.

The reversible phase of endothelial dysfunction might be a target of interventional strategies.[11] Clarkson et al. showed that L-arginine boosts endothelium-dependent dilatation.[36] Mancini et al. studied the impact of ACE inhibitors on reversible endothelial dysfunction in patients with coronary artery disease in the Trial on Reversing Endothelial Dysfunction (TREND) study.[37] A meta-analysis established that treatment with niacin improves endothelial function.[38] Other drugs studied for their role in endothelial dysfunction include atenolol, lacidipine, irbesartan, and valsartan.[39],[40] HMG-CoA reductase inhibitors (statins, e.g., atorvastatin, cervistatin, and simvastatin) have gained popularity in NS due to their proven role in hypercholesterolemia which correlates with endothelial dysfunction. Statins are shown to reduce PAI-1 and significantly improve FMD.[41],[42] Therapy with statins lead to substantial improvement in dyslipidemia in adult patients with NS, but have unproven value in changing long-term cardiovascular outcomes for pediatric patients.[43] A well-designed longitudinal study is required to understand the role of early treatment with statins in pediatric patients with FRNS/SDNS and SRNS with significant endothelial dysfunction.


  Conclusion Top


Children with FRNS/SDNS and SRNS have significant endothelial dysfunction in all stages of disease in varying severity as reflected by the levels of endothelial markers. Our study was limited by its small sample size and lack of long-term follow-up for cardiovascular outcomes. We did not assess FMD, cIMT, and markers of cardiovascular morbidity to assess the functional impact of the elevated endothelial markers.

Acknowledgment

We acknowledge the contribution of Professor Vineeta Batra, GB Pant Hospital, New Delhi, in histopathological examination of the samples.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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