{'fraction_non_alphanumeric': 0.04276388581544589, 'fraction_numerical': 0.017979641513609205, 'mean_word_length': 5.259349030470914, 'pattern_counts': {'":': 0, '<': 13, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 1, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Hypertension/prehypertension and its determinants in pediatric IgA nephropathy

Supplemental Digital Content is available in the text


Introduction
Immunoglobulin A nephropathy (IgAN), the most common primary glomerular disease worldwide in adults and children, is mesangial proliferative glomerulonephritis characterized by predominant mesangial IgA deposits. Initially considered a benign condition, IgAN is increasingly recognized as a form of glomerulonephritis with progressive potential. The long-term prognosis of IgAN substantially varies among individuals; whereas some patients have only asymptomatic microscopic hematuria for many years, up to 40% of patients progress to endstage renal disease (ESRD), necessitating renal replacement treatment (dialysis or kidney transplantation) within 10 to 20 years after a renal biopsy. [1] A growing number of studies have identified the prognostic value of clinicopathological characteristics in patients with IgAN. Besides renal lesion-related parameters such as severe proteinuria, impaired renal function, and advanced histopathological findings at the time of diagnosis, hypertension (HT) is an independent risk factor for IgAN progression and a strong predictor of poor prognosis. [2] Children with chronic kidney disease (CKD), unlike adults, most often present with secondary HT, as blood pressure (BP) elevation predominantly is a sequela of CKD [3] that is, secondary HT is a common consequence of renal damage and decreased renal function. [4] However, there are very limited data on secondary HT, and even lesser data on prehypertension (pre-HT), in the pediatric population. Our preliminary study found that secondary HT and pre-HT (HT/pre-HT) were observed in children with IgAN, [5] although the factors that are independently associated with HT/pre-HT are not known. CKD-associated HT/pre-HT needs to be controlled to prevent significant renal deterioration and excessive cardiovascular morbidity and mortality. Therefore, in this study, we aimed to investigate the risk factors for renal HT/ pre-HT in pediatric patients with IgAN and identify more effective therapeutic targets to facilitate early intervention.

Patients
This study retrospectively included 108 pediatric patients with renal biopsy-proven IgAN, diagnosed at our center from 2006 to 2013; the diagnostic criterion of IgAN was the predominant deposition of IgA immune complexes in the glomerular mesangium without evidence of systemic disease. BP was measured by the auscultatory method in the right upper arm with a sphygmomanometer (Jiangsu Yuyue Medical Equipment & Supply Co., Ltd.; size: 350 mm Â 92 mm Â 50 mm) using a standard protocol. [6] BP measurements were recorded on 3 consecutive days after admission We disregarded the first measure and the average of the second and third BP measurements was recorded as the patients BP. Both pre-HT (systolic blood pressure [SBP]/diastolic blood pressure [DBP] ≥120/80 mmHg) and HT (SBP/DBP ≥140/90 mm Hg) were defined using the age-, gender-, and height-specific BP percentile algorithm recommended by the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (2004 Working Group [7] (Patients were classified as those with HT/pre-HT (HT/pre-HT group) and without HT/pre-HT (non-HT/pre-HT group) for a comparative analysis in this study. The study protocol was approved by the institutional review board of the Beidaihe Rehabilitation and Recuperation Center of PLA (approval no. 20130136). Informed consent, for the use of clinical or pathologic data in future studies, was obtained from a parent or legal guardian of each patient at the time of the renal biopsy. Children with other secondary forms of HT were excluded from the study. Exclusion criteria included renal parenchymal abnormalities (polycystic renal disease, multicystic dysplastic renal disease, hydronephrosis, and chronic pyelonephritis), renovascular abnormalities (renal artery stenosis or thrombosis, and renal vein thrombosis), iatrogenic causes (corticosteroids, decongestants, and caffeine), childhood tumors associated with hypertension (Wilms tumor, neuroblastoma and pheochromo cytoma), as well as endocrinopathies associated with HT (hypercortisolism, hyperthyroidism, hyperaldosteronism, diabetes and congenital adrenal hyperplasia [8] )

Treatment and response evaluation
To evaluate therapeutic management and patient response, we collected prescriptions from the patients during follow-up. Prescriptions included agents for renin-angiotensin-aldosterone system blockade (angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin receptor blockers [ARBs]), dihydropyridine (DHP)-calcium channel blockers (CCBs), a1/b1-adrenergic receptor blockers, corticosteroids, other immunosuppressive agents (cyclophosphamide, mycophenolate mofetil, and lefunomide), and antithrombotics (antiplatelet drugs, anticoagulants, and thrombolytics). We used the following definitions for outcomes analysis. complete remission: normal urine, BP, and renal function at follow-up; partial remission: asymptomatic hematuria and/or proteinuria (proteinuria <1 g/day) as well as the absence of peripheral edema, HT, and renal dysfunction at follow-up; progression of CKD: an increase in proteinuria (proteinuria ≥1 g/ day) and/or uncontrolled HT and/or elevated SCr level (SCr <442 mmol/L); and ESRD: elevated SCr ≥442 mmol/L. [16]

Treatment protocol
The treatment protocol of the study is provided in Supplementary Table 1, http://links.lww.com/MD/E892. We considered corticosteroid therapy in patients with persistent proteinuria ≥1 g/d after supportive therapy for >3 months. The patients with nephrotic syndrome or a relative amount of crescents, as well as an acute tubulointerstitial lesion on a kidney biopsy, might consider adding corticosteroid directly. Immunosuppressors were considered if patients presented with persistent nephrotic syndrome or significant crescent formation (cyclophosphamide, mycophenolate mofetil, and leflunomid), or progressive decline in renal function (cyclophosphamide) after corticosteroid therapy. Immunosuppressors (leflunomide) were considered alone if the patients with persistent proteinuria ≥1 g/d refused the use of corticosteroid because of poor response depending on the patients intention. Initially, patients used prednisone (0.8-1 mg/kg. d; maximum, 60 mg/d) for 2 months, which was tapered to 5 mg every 2 weeks and stopped within 6 to 8 months. Another regimen of corticosteroid therapy was high-dose intravenous methylprednisolone pulse therapy (500 or 250 mg/d for 3 successive days, partially repeated 3 times within 3 weeks), which was determined by the treating physician, followed by a standard dose of prednisone. Overall, more patients with nephrotic syndrome required intensive immunosuppressive therapy compared with patients with non-nephrotic syndrome. Furthermore, other medications (ACEIs or ARBs, DHP-type CCBs, a1/b1-adrenergic receptor blockers, diuretics, antithrombotics, and other drugs to promote blood circulation and clear blood stasis) were determined by the treating physician. All patients were followed up for 6 months or longer. All medications used during the study period were recorded.

Statistical analysis
Continuous variables are presented as mean ± standard deviation or median (minimum-maximum) and were compared using an independent sample t-test or Mann-Whitney U test. Categorical variables are expressed as frequencies with percentages, and were compared using the Chi-Squared test, Mann-Whitney U test, or Kruskal-Wallis test. Univariate and multivariate logistic regression analyses were conducted to determine risk factors for HT/pre-HT in patients with IgAN. Results were expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs). Correlations were tested by Spearmans correlation coefficient. P < .05 was considered indicative of statistically significant differences. Statistical analyses were undertaken in SPSS 12.0 (Chicago, IL, USA).

Clinical presentation
There were 73 boys and 35 girls with an overall mean age of 12.57 ± 3.01 years. Of the 108 patients enrolled in this study, 48 patients (44.44%) had the nephrotic syndrome, 32 (29.63%) had hematuria, and proteinuria (proteinuria <50 mg/kg), and 16 (14.81%) had chronic glomerulonephritis at the time of renal biopsy. Patients with isolated hematuria (8.33%), isolated proteinuria (1.85%), and acute glomerulonephritis (0.93%) constituted only a minor proportion of our study population. No patient had rapidly progressive glomerulonephritis. We found HT/pre-HT as an initial sign of IgAN in 21 of 108 (19.44%) patients; moreover, nephrotic syndrome was present in 42.86% and 44.83% of patients with and without HT/pre-HT, respectively. The hematuria-proteinuria sign was reported in 38.10% and 27.59% of patients with and without HT/pre-HT, respectively. Apart from these patients, 19.05% and 13.79% of patients with and without HT/pre-HT, respectively, had chronic glomerulonephritis. However, the between-group differences in presenting symptoms were not significant for the HT/pre-HT and non-HT/pre-HT groups (P = .297, Table 1).

Risk factors for HT/pre-HT
The baseline clinical and pathological features are provided in Supplementary Table 2, http://links.lww.com/MD/E893 and Table 1 Clinical presentation at the time of renal biopsy in IgAN patients with and without HT/pre-HT.    (Fig. 1).

Correlation of segmental glomerulosclerosis or adhesion and other pathological parameters
We did not find an association between IgG deposition and segmental glomerulosclerosis or adhesion (P = .079), while the association between intensity of IgA deposits and segmental glomerulosclerosis or adhesion was not considered due to low correlation coefficient (r = 0.199). However, the underlying cause of segmental sclerosis or adhesion might be correlated with different histological features such as glomerular crescents (r = 0.456, P < .01), Lees grades (r = 0.454, P < .01), renal arteriolar wall thickening (r = 0.337, P < .01), and endocapillary hypercellularity (r = 0.306, P = .001) ( Table 6).

Association of IgA deposition with coagulation variables
We used direct immunofluorescence (IF) to examine glomerular deposits of fibrinogen, and 50 of the 108 patients (46.30%) had high IF scores (1 + , n = 33; 2 + , n = 17). Fibrinogen was present in both the mesangium and glomerular capillary loops, but not exclusively in the mesangium (Table 7). This confirms that IgAN involves a coagulation process that leads to fibrin formation in the glomerulus. [17][18][19] Furthermore, the intensity of IgA deposits, an important marker of pathogenetic activity in IgAN, was significantly correlated with the intensity and location of fibrinogen deposits (intensity: r = 0.291, P = .002; location: r = 0.275, P = .004) ( Table 8). The location of IgA deposits and the intensity or location of fibrinogen deposits were not significantly associated (Table 9).

Discussion
Compared to adults, there is a higher incidence of a secondary cause for HT in pediatric patients, and CKD is considered a   www.md-journal.com common cause of pediatric secondary HT. [20,21] CKD and HT are intimately connected, and synergistically induce a further decline in renal function. Both HT and pre-HT are frequently underdiagnosed in the pediatric CKD population. [22] We found that 5 of the 21 patients with HT/pre-HT were not on antihypertensives, indicating that a proportion of these patients could be undiagnosed, especially those with pre-HT. This condition going undiagnosed could be attributed to a lack of adequate awareness of pre-HT. Furthermore, complete remission was more common in normotensive children compared to those with HT/pre-HT despite the absence of significant differences in clinical presentation between HT/pre-HT and non-HT/pre-HT; this suggests better short-term outcomes in the non-HT/pre-HT patients compared to those with HT/pre-HT. It was markedly apparent that HT/pre-HT secondary to IgAN significantly influenced the clinical prognosis of pediatric patients, even with regard to short-term outcomes. Therefore, it is imperative to emphasize HT/pre-HT at renal biopsy as an important indicator for treatment and renoprotection. Early diagnosis of elevated BP, especially through early recognition of pre-HT, will help formulate an intervention strategy, and improved BP control may slow the relentless progression of CKD.
We analyzed antihypertensive pharmacotherapy in patients with IgAN, and found significant between-group differences in the use of a1/b1-adrenergic receptor blockers and DHP-type CCBs in the HT/pre-HT and non-HT/pre-HT groups; however, there were no significant differences in ACEI, ARBs, or diuretic use. These results indirectly indicate that sympathetic overactivation and vasoconstriction may be more likely to be identified as important etiopathogenetic factors in secondary HT/pre-HT. We found that ACEIs/ARBs and diuretics were used very frequently, especially for the antiproteinuric and renoprotective efficacy of ACEIs/ARBs, even in non-HT/pre-HT patients.
Univariate analysis showed that many clinical and pathological elements were associated with HT/pre-HT. However, multivariate analysis found that only age, SCr, PT, and segmental glomerulosclerosis or adhesion maintained their independent association. PT served as the basis for therapy with antithrombotics and drugs to promote blood circulation and clear blood stasis. PT might be a potential therapeutic target for early intervention in IgAN patients, especially those with HT/pre-HT. Segmental glomerulosclerosis or adhesion is an adverse prognostic factor in the progression of IgAN [23] ; however, its significance in secondary HT/pre-HT has not been elucidated yet. We verified segmental glomerulosclerosis or adhesion as a risk factor for HT/ pre-HT in patients with IgAN, and it was the only histological factor independently associated with HT/pre-HT. Thus, we infer segmental glomerulosclerosis or adhesion, a common morphologic pattern of injury, plays a pivotal role in HT/pre-HT secondary to IgAN, and requires conservative management that aims for control of BP. Our study showed that the co-deposition of IgM was similar in patients with or without segmental glomerulosclerosis lesion, although primary focal segmental glomerulosclerosis was characterized by diffuse predominant mesangial IgM deposits. Segmental sclerosis or adhesion in IgAN, a chronic lesion on the new MEST-C score, [15] may occur as a consequence of distinct processes. We found segmental glomerulosclerosis or adhesion was associated with different histological features, including Lee's grades, endocapillary hypercellularity, glomerular crescents, and renal arteriolar wall thickening. Our findings support a variety of etiopathogenetic mechanisms for segmental glomerulosclerosis or adhesion, including sequelae of previously active lesions (endocapillary hypercellularity and glomerular crescents), and hemodynamic changes (renal arteriolar wall thickening). [24] Moreover, these observations may indicate targets for improving segmental glomerulosclerosis or adhesion. Active lesions or segmental sclerosis can be partially prevented by corticosteroid and/or immunosuppressive regimens, which help control secondary HT/pre-HT. Mesangial IgA deposits are the initiating event in the pathogenesis of IgAN; although IgM, IgG, and complement components are often codeposited, they are not essential for disease activity or progression. Deposits of IgA alone seem adequate to provoke glomerular injury in susceptible individuals. [25] Moreover, we found that the intensity of IgA deposits had a significant positive association with the intensity and location of fibrinogen deposits. These observations potentially indicate that novel therapeutic targets in controlling secondary HT/pre-HT and slowing the progression of IgAN should not only focus on decreasing active lesions, but also on improving hemodynamics and coagulation status, together with decreasing IgA accumulation.
The main limitation of the present study is its retrospective observational nature, which precludes the establishment of a cause-effect relationship. Moreover, the study sample was relatively small and from a single center and had a short follow-up period, given the relentless silent progression of IgAN. Despite these limitations, the current study suggests important risk factors and new therapeutic targets for HT/pre-HT.
In conclusion, HT/pre-HT are frequently present in IgAN. Age, SCr, PT, and segmental glomerulosclerosis or adhesion are independent risk factors for IgAN with HT/pre-HT. Furthermore, segmental glomerulosclerosis or adhesion is associated with pathological findings, such as endocapillary hypercellularity, glomerular crescents, and renal arteriolar wall thickening. The intensity of IgA deposits was significantly associated with the intensity and location of fibrinogen deposits. We emphasize that potential therapeutic approaches for IgAN with HT/pre-HT might be directed toward the management of coagulation status, active lesions, and hemodynamics. A. Lees grades in IgAN patients with and without segmental glomerulosclerosis or adhesion (S0 vs S1, P < .01: Grades I + II of S0 vs Grades I + II of S1, P < .01; Grade III of S0 vs Grade III of S1, P = .003; Grades IV + V of S0 vs Grades IV + V of S1, P = .016). B. Endocapillary hypercellularity in IgAN patients with and without segmental glomerulosclerosis or adhesion (S0 vs S1, P = .001). C. Glomerular crescents in IgAN patients with and without segmental glomerulosclerosis or adhesion (S0 vs S1, P < .01: C0 of S0 vs C0 of S1, P < .01; C1 of S0 vs C1 of S1, P < .01). D. Renal arteriolar wall thickening in IgAN patients with and without segmental glomerulosclerosis or adhesion (S0 vs S1, P < .01). IgAN = Immunoglobulin A nephropathy.   Table 8 Correlation between intensity of IgA deposits and fibrinogen deposits in patients with IgAN.