Outcome of immunosuppression in children with IgA vasculitis-related nephritis.

BACKGROUND AND HYPOTHESIS: IgA vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Treatment recommendations are, due to a lack of evidence, based on expert opinion resulting in variation. The aim of this study was to describe clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy proven IgAVN to identify prognostic risk factors and signals of treatment efficacy. METHODS: Retrospective data were collected on 1148 children with biopsy proven IgAVN between 2005 and 2019 from 41 international paediatric nephrology centres across 25 countries and analyzed using multivariate analysis. The primary outcome was estimated glomerular filtration rate (eGFR) and persistent proteinuria at last follow up. RESULTS: The median follow up was 3.7 years (IQR 2-6.2). At last follow up, 29% of patients had an eGFR < 90 ml/min/1.73m2, 36% had proteinuria and 3% had chronic kidney disease stage 4-5. Older age, lower eGFR at onset, hypertension and histological features of tubular atrophy and segmental sclerosis were predictors of poor outcome. There was no evidence to support any specific second line immunosuppressive regimen to be superior to others, even when further analysing subgroups of children with reduced kidney function, nephrotic syndrome or hypoalbuminemia at onset. Delayed start of immunosuppressive treatment was associated with a lower eGFR at last follow up. CONCLUSION: In this large retrospective cohort, key features associated with disease outcome are highlighted. Importantly there was no evidence to support that any specific immunosuppressive treatments were superior to others. Further discovery science and well-conducted clinical trials are needed to define accurate treatment and improve outcomes of IgAVN.

The incidence and prevalence of IgA nephropathy in Europe.

BACKGROUND: This study aimed to determine the incidence and prevalence of immunoglobulin A nephropathy (IgAN) in Europe based on high-quality data from national registries. METHODS: IgAN incidences were obtained from a literature review of European studies of national kidney biopsy registry data in which IgAN diagnosis was biopsy-verified using contemporary techniques. Studies were eligible for the main analysis if published from 1990 to 2020. IgAN point prevalence was defined as the annual IgAN incidence multiplied by the estimated duration of disease. Incidence and prevalence estimates were made for three pooled populations: (i) patients of all ages; (ii) pediatric patients; and (iii) elderly patients. RESULTS: Across 10 European countries, the estimated annual IgAN incidence was 0.76 per 100 000 in patients of all ages. The corresponding pooled IgAN point prevalence was 2.53 per 10 000 (95% confidence interval: 2.51-2.55), ranging from 1.14 per 10 000 in Spain to 5.98 per 10 000 in Lithuania. Applied to 2021 population estimates, the number of expected prevalent IgAN cases was 47 027 across all 10 countries and ranged from 577 in Estonia to 16 645 in Italy. Among pediatric patients, IgAN incidence was 0.20 per 100 000 children and IgAN point prevalence was 0.12 per 10 000 children. Among elderly patients, IgAN incidence was 0.30 per 100 000 and IgAN point prevalence was 0.36 per 10 000. CONCLUSIONS: Based on high-quality data from European national registries, IgAN point prevalence was estimated at 2.53 per 10 000 in patients of all ages. Prevalence was considerably lower in pediatric and elderly populations.

How to take advantage of easily available biomarkers in patients with IgA nephropathy: IgA and C3 in serum and kidney biopsies.

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. It is diagnosed based on clinical and histological features including predominant IgA deposits in kidney biopsy. The multi-hit theory, based on the production of GDIgA1 and anti-GDIgA1 antibodies, and complement activation via alternative and lectin pathways and also a genetic tendency are crucial in the pathogenesis of IgAN. The aim of the present review is to summarize the utility of routine diagnostic tests in IgA nephropathy, such as IgA and C3 in serum and kidney biopsy specimens, for predicting the disease progression. The paper also contains data on new markers used in the diagnosis and prognosis of IgA nephropathy.

A rare cause of steroid-resistant nephrotic syndrome - a case report.

Steroid resistance is a common condition occurring in children with nephrotic syndrome. Until now, over 50 genes involved in steroid-resistant nephrotic syndrome (SRNS) pathogenesis have been identified, among which the most prevalent are NPHS1, NPHS2, CD2AP, and PTPRO. The patterns of inheritance of SRNS are autosomal recessive, autosomal dominant, or mitochondrial, and tissues of those patients show focal segmental glomerulosclerosis (FSGS) signs in histopathological image analysis. We present a case of a 6-year-old girl who was admitted to the pediatric nephrology department due to nephrotic range proteinuria and edema of the lower leg. We started therapy with prednisone at a dose of 45 mg (60 mg/m2), enalapril as a nephroprotection, and antihistamines as an additional treatment. During in-patient treatment, we detected increased blood pressure. Due to persistent proteinuria in spite of 6-week treatment with steroids at the maximal dose, we confirmed disease resistance to steroids. Additionally, FSGS signs were confirmed in kidney biopsy samples. After genetic screening for SRNS and detection of the rare gene mutation NUP93 we reduced prednisone but maintained nephroprotective treatment and administered cyclosporin A. The girl remains currently under the care of nephrologists with normal arterial blood pressure, trace proteinuria in follow-up examination, and normal kidney function. NUP93 mutation is extremely rare; therefore few cases have been described to date. The onset of the symptoms in all pediatric patients appeared before the age of 8 and they developed end stage kidney disease (ESKD). They might manifest symptoms from the other systems.

The switch from proteasome to immunoproteasome is increased in circulating cells of patients with fast progressive immunoglobulin A nephropathy and associated with defective CD46 expression.

The proteasome to immunoproteasome (iPS) switch consists of ß1, ß2 and ß5 subunit replacement by low molecular weight protein 2 (LMP2), LMP7 and multicatalytic endopeptidase-like complex-1 (MECL1) subunits, resulting in a more efficient peptide preparation for major histocompatibility complex 1 (MHC-I) presentation. It is activated by toll-like receptor (TLR) agonists and interferons and may also be influenced by genetic variation. In a previous study we found an iPS upregulation in peripheral cells of patients with immunoglobulin A nephropathy (IgAN). We aimed to investigate in 157 IgAN patients enrolled through the multinational Validation Study of the Oxford Classification of IgAN (VALIGA) study the relationships between iPS switch and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling. Patients had a previous long follow-up (6.4 years in median) that allowed an accurate calculation of their slope of renal function decline. We also evaluated the effects of the PSMB8/PSMB9 locus (rs9357155) associated with IgAN in genome-wide association studies and the expression of messenger RNAs (mRNAs) encoding for TLRs and CD46, a C3 convertase inhibitor, acting also on T-regulatory cell promotion, found to have reduced expression in progressive IgAN. We detected an upregulation of LMP7/ß5 and LMP2/ß1 switches. We observed no genetic effect of rs9357155. TLR4 and TLR2 mRNAs were found to be significantly associated with iPS switches, particularly TLR4 and LMP7/ß5 (P < 0.0001). The LMP7/ß5 switch was significantly associated with the rate of eGFR loss (P = 0.026), but not with eGFR at biopsy. Fast progressors (defined as the loss of eGFR >75th centile, i.e. -1.91 mL/min/1.73 m2/year) were characterized by significantly elevated LMP7/ß5 mRNA (P = 0.04) and low CD46 mRNA expression (P < 0.01). A multivariate logistic regression model, categorizing patients by different levels of kidney disease progression, showed a high prediction value for the combination of high LMP7/ß5 and low CD46 expression.

Treatment of idiopathic nephrotic syndrome with two steroid dosing regimens - one-year observational study.

INTRODUCTION: The aim of the study was to compare the first year of disease in children with idiopathic nephrotic syndrome (INS) treated according to two prednisone dosing regimens: a weight-based schedule (2 mg/kg/24 h in the 1st month, 2 mg/kg/48 h in the 2nd month, with dose tapering during the following 4 months), and a body surface area (BSA)-based schedule (60 mg/m2/24 h in the 1st month, 40 mg/m2/48 h in the 2nd month, with dose tapering during the following 4 months). MATERIAL AND METHODS: In 2 groups of children treated with weight- and BSA-based regimens (20 patients, 3.13 ±1.01 years, treated in 2010-2013 and 20 patients, 5.13 ±2.86 years, treated in 2014-2016) clinical and anthropometrical parameters, number of INS relapses, total prednisone dose (mg/kg/year), and steroid adverse effects were compared during the first year of disease. RESULTS: Children treated with the weight-based steroid regimen received a higher total annual prednisone dose (259.06 ±79.54 vs. 185.83 ±72.67 mg/kg/24 h, p = 0.004) and had a shorter (though not significantly) period without prednisone (38.25 ±55.83 vs. 75.90 ±73.06 days, p = 0.062) compared to patients treated with the BSA-based regimen. There was no difference in number of relapses between groups (2.20 ±1.64 vs. 1.60 ±1.67, p = 0.190) but more patients relapsed in the weight-based group (19/20 vs. 13/20, p = 0.044). No differences in Z-score values of height, weight, and body mass index (BMI) were observed. No steroid-related adverse events were noted except for arterial hypertension (4/20 vs. 5/20 patients, p = 1.000). CONCLUSIONS: The BSA-based regimen of prednisone dosing in children with INS reduces exposure to steroids and risk of relapse, as well as increases days off steroids in the first year compared to the weight-based regimen with a high second-month dose.

Relationship between Gd-IgA1 and TNFR1 in IgA nephropathy and IgA vasculitis nephritis in children - multicenter study.

AIM OF THE STUDY: To evaluate the relationship between serum Gd-IgA1 (sGd-IgA1) and serum and urine TNFR1 (sTNFR1, uTNFR1) levels as possible prognostic factors in IgA nephropathy (IgAN) and IgA vasculitis nephritis (IgAVN). MATERIAL AND METHODS: From 299 patients from the Polish Registry of Pediatric IgAN and IgAVN, 60 children (24 IgAN and 36 IgAVN) were included in the study. The control group consisted of 20 healthy children. Proteinuria, haematuria, serum creatinine as well as IgA and C3 levels were measured and glomerular filtration rate (GFR) was calculated at onset and at the end of the follow-up. Kidney biopsy findings were evaluated using the Oxford classification. Serum Gd-IgA1 and serum and urine TNFR1 levels were measured at the end of follow-up. RESULTS: Serum Gd-IgA1 level was significantly higher in IgAN and IgAVN patients in comparison to the control group. Urine TNFR1 was significantly higher in IgAN than in IgAVN and the control group. We did not observe any differences in sTNFR1 level between IgAN, IgAVN and control groups. We found a positive correlation between Gd-IgA1 and creatinine (r = 0.34), and negative between Gd-IgA1 and GFR (r = -0.35) at the end of follow-up. We observed a negative correlation between uTNFR1/creatinine log and albumin level and protein/creatinine ratio. We did not find any correlations between Gd-IgA1 and TNFR1. CONCLUSIONS: The prognostic value of sGd-IgA1 in children with IgAN and IgAVN has been confirmed. TNFR1 is not associated with Gd-IgA1 and is not a useful prognostic marker in children with IgAN/IgAVN and normal kidney function.

[Accidentally diagnosed distal renal tubular acidosis with nephrocalcinosis - a case report]. / Przypadkowo rozpoznana kwasica kanalikowa dystalna z nefrokalcynoza ­ opis przypadku.

Distal renal tubular acidosis is a defect of acidification of urine in distal tubule. Full-blown form is characterized by polyuria, growth deficiency, nephrolithiasis or nephrocalcinosis. Mutations in genes encoding Cl-/HCO3 - exchanger (autosomal dominant) or H+-ATPase (autosomal recessive) are the most frequent in children. A CASE REPORT: In a boy aged 2,5 years, healthy, with proper development, metabolic acidosis with hyperchloremia, hypokalaemia, normal glomerular filtration rate and alkaline urine was discovered during hospitalization because of pneumonia. USG showed normal length kidney with nephrocalcinosis type IIB. The family history revealed nephrocalcinosis on the part of the boy's father. He also had metabolic acidosis in blood gas test. Genetic test in a boy and his father showed mutation of SLC4A1(17q21-q22) gene encoding Cl-/HCO3 - exchanger. The boy was treated with 8,4% NaHCO3 - orally (1mEq/kg/24h) and KCl (0,3 mEq/kg/24h). We obtained normalization of blood gas test and potassium concentration. CONCLUSIONS: Every child, with accidentally discovered metabolic acidosis, even with normal development, should be diagnosed in case of renal tubular acidosis. Electrolytes, gas blood test, urinalysis and USG are needed in the closest family members of child with diagnosed renal tubular acidosis.

[Does Gordon's syndrome always manifest as hypertension? - a case report of one family]. / Czy zespól Gordona zawsze przebiega w postaci nadcisnienia tetniczego? ­ opis przypadku jednej rodziny.

Gordon's syndrome (pseudohipoaldosteronism type II) is a genetically determined, autosomal dominant type of monogenic hypertension caused by excessive reabsorption of chlorine accompanied by reabsorption of sodium and water. CASE REPORTS: The case of a family (2 brothers: 12 and 16 years old and their father), in whom genetic tests confirmed the presence of a mutation characteristic of Gordon syndrome, despite the absence of hypertension in boys. Diagnostics of the family started with a 12-year-old boy because of observed for 2 years hyperkalemia and delayed growth and puberty. The physical examination showed low height (<3c), discreet facial dysmorphic features (close spaced eyelid cracks, low-set ears) and lack of puberty, arterial pressure was normal. In laboratory tests, apart from hyperkalaemia at normal sodium level, hyperchloremia and metabolic acidosis were found. Plasma renin activity and aldosterone concentration were normal. There were no glomerular filtration abnormalities, renal parameters and kidney image in ultrasound examination were normal. Hyperkalemic tubular acidosis type IV was diagnosed and oral treatment with sodium bicarbonate was started. Due to the inability to achieve acidosis control with sodium bicarbonate and positive family history of hyperkalaemia and hypertension in the boy's father, the suspicion of Gordon syndrome was raised. Simultaneously, in the studies performed in the 16-year-old brother of the patient hyperkalemic acidosis, normal blood pressure and growth within normal limits for sex and age were found. The treatment of boys and father with hydrochlorothiazide was started, which resulted in the equalization of acidosis and calemia and rapid normalization of blood pressure in the father. CONCLUSIONS: In patients with tubular hyperkalemic acidosis, despite the absence of hypertension, Gordon's syndrome should be considered in the differentiation.

[Cerebral salt wasting syndrome as a complication of subarachnoid hemorrhage in a girl with nephrotic syndrome - a case report]. / Mózgowy zespól utraty soli jako powiklanie krwawienia podpajeczynówkowego u dziewczynki z zespolem nerczycowym ­ opis przypadku.

INTRODUCTION: Cerebral salt wasting syndrome (CSWS), characterized by natriuresis, polyuria, and hypovolemia, is a rare complication of central nervous system injury or disease. A CASE STUDY: 12-year-old girl was admitted with second attack of nephrotic syndrome (NS). On admission she presents with edema, blood pressure 110/60 mm Hg, proteinuria 145 mg/kg/24h, hypoalbuminemia (1.7 g/dL), GFR 94.4 mL/min/1.73m2, sodium 133 mmol/L. On 5th day the patient developed thrombosis of right subclavian and axillary vein and was treated with recombinant tissue plasminogen activator (0.3 mg/kg/h i.v.). 45 minutes after onset of the infusion severe headache appeared. Computed tomography revealed subarachnoid hemorrhage in a region of left occipital lobe and posterior 1/3 part of sickle of the brain. Control ultrasonography examination revealed resolution of the thrombus. No deficits were found on neurologic examination. Proteinuria subsided on 11th day of hospitalization. After the hemorrhage hypovolemia, hypotension (80/40 - 100/60 mm Hg, heart rate 100/min), polyuria, and pathologic natriuresis (up to 13.0 mmol/kg/24h) were observed. Cerebral salt wasting syndrome was recognized. The girl was supplemented with oral and intravenous sodium (up to 10 mmol/ kg/24h). In following days gradual decrease of diuresis and urinary sodium loss was observed. The patient was discharged home after 41 days with normal diuresis (1.5l/24h) and natriuresis (1.44 mmol/kg/24h). CONCLUSIONS: Treatment of thromboembolic complications in children with NS poses a risk of central nervous system bleeding. Serum sodium concentration and diuresis must be strictly monitored in patients with central nervous system lesion, especially in the course of nephrotic syndrome.

Asymmetric dimethylarginine is not a marker of arterial damage in children with glomerular kidney diseases.

INTRODUCTION: Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, correlates with cardiovascular risk especially in patients with chronic kidney disease. The aim of our study was to establish significance of ADMA as a biomarker of arterial damage in children with glomerulopathies. MATERIAL AND METHODS: In 80 children with glomerulopathies (mean age, 11.33 ±4.25 years; 42 with idiopathic nephrotic syndrome [INS], 38 with IgA or Henoch-Schoenlein nephropathy [IgAN/HSN]), we analyzed serum ADMA [nmol/ml], peripheral and central blood pressure, arterial stiffness (augmentation index - AIx75HR, pulse wave velocity - PWV), common carotid artery intima media thickness (cIMT), and selected clinical and biochemical parameters. RESULTS: In the study group, mean ADMA concentration was 1.66 ±1.19 [nmol/ml] and did not differ between INS and IgAN/HSN patients. We found no significant correlations between concentration of ADMA, cIMT [mm]/Z-score, PWV [m/s]/Z-score, and AIx75HR [%] in the whole group and in INS and IgAN/HSN patients. In the whole group of 80 children, ADMA correlated (p < 0.05) with BMI Z-score (r = -0.24), uric acid (r = -0.23), HDL-cholesterol (r = -0.25), and central mean arterial pressure (r = -0.25), in children with INS also with total protein (r = 0.37), albumin (r = 0.36), and total cholesterol (r = -0.40, p = 0.028). In multivariate analysis, serum albumin was the strongest determinant of ADMA in the whole group (ß = 0.536, 95% CI: 0.013-1.060, p = 0.045). CONCLUSIONS: 1. In children with glomerulonephritis, measurement of asymmetric dimethylarginine cannot replace well established and validated methods of assessment of subclinical arterial damage. 2. In children with glomerular kidney diseases, ADMA concentration is related primarily to serum albumin concentration.

[Pulmonary embolism in a girl with nephrotic syndrome and factor V Leiden - case report]. / Zatorowosc plucna u dziewczynki z zespolem nerczycowym i czynnikiem V Leiden ­ opis przypadku.

Thromboembolic complications are found in 2-3% of children with nephrotic syndrome (NS); this increased risk is caused by hypovolemia, hemoconcentration, increased number and activity of platelets, hyperfibrinogenemia and loss of coagulation inhibitors. Risk is even higher in case of additional factors e.g. congenital thrombophilia. CASE REPORT: Girl with NS aged 17 11/12 years was admitted to hospital due to respiratory tract infection with cough and back pain. NS started 9 months earlier and she had two bouts of disease, and was treated only with prednisone (current dose - 60 mg/48h). On admission she was without any abnormalities on auscultation, with BP 111/65 mmHg, HR 80 bpm, satO2 99%. Lab results showed the increase of WBC 18.3×103/µL, D-dimers 23038 µg/L and proteinuria 900 mg/dL. Other values of examined parameters were in normal limits. Chest X-ray and ECG were also normal. Presumptive diagnosis of pulmonary embolism was made and the patient was given 1000IU of antithrombin III and nadroparine (2x90IU/kg/24h s.c.). In ECHO the occlusion of left pulmonary artery and preserved blood flow in right were revealed. In angioCT clot nearly filling lumen of left pulmonary artery, clot in intermediate part of right pulmonary artery, and focus of pulmonary infarction in 10th segment of left lung were found. Doppler USG of lower limb veins did not reveal thrombi or perforator vein incompetence. Treatment with nadroparine was continued, and rapid improvement of clinical condition and disappearance of pain and cough were observed. Mycophenolate mofetil was added, which resulted in subsidence of proteinuria. Rivaroxaban was used in prophylaxis of recurrences of thromboembolism. Tests for thrombophilia revealed factor V Leiden in patient.

[Influence of intensity, localization and type of deposits in renal biopsy for disease symptoms and follow up in children with IgA nephropathy]. / Wplyw nasilenia, lokalizacji i rodzaju zlogów w biopsji nerki na objawy kliniczne i rokowanie u dzieci z nefropatia IgA.

IgA nephropathy is the most common glomerulonephritis in the world. For diagnosis kidney biopsy is necessary. AIM: The aim of the study was assessment the significance of IgA, C3 and IgG deposits intensity and location in kidney childhood IgA nephropathy (IgAN) for the symptoms of the disease and the follow up. MATERIALS AND METHODS: Study population consisted of 81 children, average 11,45±3,99 years. IgAN was recognized based on renal biopsy, performed 1,2±1,84, median 0,5 years after the onset. We used Oxford classification (OC) to assess the severity of histopatological lesions. In renal biopsy IgA and C3 deposits were found in immunofluorescence in mesangium or in vessels of glomeruli or both, and intensity was defined 0 to +4. We analyzed: proteinuria (mg/kg/day), hematuria, creatinine, GFR (according to Schwartz formula) two times, at the onset of the disease (OOD) and at the follow up (FU). Patients were treated with: ACEI/ARB or steroids alone or with imunossupresion drugs: azathioprine (AZA), cyclophosphamide (CYC), cyclosporine A (CsA), mycopnenolate mophetil (MMF). The follow up was 3,31±2,88 years. We divided the patients into two groups, depending on the intensity of IgA deposits: G1 n=29 (+1/+2), G2 n=52 (+3/+4); depending on the localizations of these deposits, we analyzed 3 groups: A n= 39 (mesangium), B n= 15 (glomeruli vessels), C n=27 (both) and depending on the kind of deposits we analyzed 4 groups: gr. a - n=30 (only IgA), gr. b - n=37 (IgA+C3), gr. c - n=5 (IgA+IgG) gr. d - n= 9 (IgA+IgG+C3). RESULTS: At OOD and FU we not found any differences in G1 vs G2 for: age, proteinuria, GFR and OC in renal biopsy; at FU GFR<90 ml/ min/1,73 m2 FU was observed more frequently in G2 vs G1 (p=0,02). The differences in groups A,B,C and groups a,b,c,d were not found. CONCLUSIONS: Poor prognosis in childhood IgAN may also depend on the intensity of the deposits, irrespective of their location.

Serum GDIgA1 levels in children with IgA nephropathy and Henoch-Schönlein nephritis.

INTRODUCTION: GDIgA1 (galactose deficient IgA1) plays a significant role in the pathogenesis of IgA nephropathy (IgAN) and Henoch-Schönlein nephritis (HSN). AIM OF THE STUDY: The aim of this study was to assess the relevance of serum GDIgA1 level as a prognostic marker in children with IgAN and HSN. MATERIAL AND METHODS: 41 children were included to the study group (15 IgAN, 26 HSN) and 22 to the control group. The following parameters were evaluated at baseline and endpoint: proteinuria, erythrocyturia, serum creatinine, serum IgA, GFR. A kidney biopsy was performed in all patients and evaluated according to the Oxford Classification (1 - present, 0 - absent: M - mesangial hypercellularity; E- endocapillary hypercellularity; S - segmental sclerosis/adhesion; T - tubular atrophy/interstitial fibrosis), and was calculated as the total score (sum of M, E, S, T). At the end of follow-up, the serum GDIgA1 concentration was measured. RESULTS: The serum GDIgA1 concentration in patients with IgAN and HSN was significantly higher than in the control group. No significant differences in mean proteinuria, erythrocyturia, GFR, MEST score, or GDIgA1 in serum, as well as the duration of follow-up between IgAN and HSN were observed. Baseline serum IgA concentration and time to kidney biopsy were significantly higher in children with IgAN than in children with HSN. We observed a positive correlation between GDIgA1 and IgA levels (r = 0.53), and GDIgA1 and serum creatinine levels (r = 0.5), as well as negative correlation between GDIgA1 and GFR (r = -0.37). CONCLUSIONS: Serum GDIgA1 level may have a prognostic value in children with IgAN and HSN; however, to fully elucidate its clinical potential further studies performed in larger patient cohorts are required.

Risk factors for progression in children and young adults with IgA nephropathy: an analysis of 261 cases from the VALIGA European cohort.

BACKGROUND: There is a need for early identification of children with immunoglobulin A nephropathy (IgAN) at risk of progression of kidney disease. METHODS: Data on 261 young patients [age <23 years; mean follow-up of 4.9 (range 2.5-8.1) years] enrolled in VALIGA, a study designed to validate the Oxford Classification of IgAN, were assessed. Renal biopsies were scored for the presence of mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T1-2) (MEST score) and crescents (C1). Progression was assessed as end stage renal disease and/or a 50 % loss of estimated glomerular filtration rate (eGFR) (combined endpoint) as well as the rate of renal function decline (slope of eGFR). Cox regression and tree classification binary models were used and compared. RESULTS: In this cohort of 261 subjects aged <23 years, Cox analysis validated the MEST M, S and T scores for predicting survival to the combined endpoint but failed to prove that these scores had predictive value in the sub-group of 174 children aged <18 years. The regression tree classification indicated that patients with M1 were at risk of developing higher time-averaged proteinuria (p < 0.0001) and the combined endpoint (p < 0.001). An initial proteinuria of ≥0.4 g/day/1.73 m2 and an eGFR of <90 ml/min/1.73 m2 were determined to be risk factors in subjects with M0. Children aged <16 years with M0 and well-preserved eGFR (>90 ml/min/1.73 m2) at presentation had a significantly high probability of proteinuria remission during follow-up and a higher remission rate following treatment with corticosteroid and/or immunosuppressive therapy. CONCLUSION: This new statistical approach has identified clinical and histological risk factors associated with outcome in children and young adults with IgAN.

Ambulatory arterial stiffness index, blood pressure variability, and nocturnal blood pressure dip in children with IgA and Henoch-Schönlein nephropathy
.

AIM: Evaluation of mean blood pressure values, ambulatory arterial stiffness index (AASI), pulse pressure (PP), blood pressure variability (BPV), and circadian blood pressure rhythm using ambulatory blood pressure monitoring (ABPM) in children with IgA nephropathy and Henoch-Schönlein nephropathy (IgAN/HSN). MATERIAL AND METHODS: In 48 children (29 with IgAN, 19 with HSN) aged 14.04 ± 3.76 years, we evaluated retrospectively 24-hour systolic and diastolic BP (24hSBP, 24hDBP), AASI, PP, systolic and diastolic BPV, and nocturnal BP dip by ABPM, body mass index (BMI) Z-score, medications, and biochemical parameters. The control group (CG) consisted of 20 healthy children aged 13.36 ± 4.12 years. RESULTS: AASI was 0.369 ± 0.100 in IgAN, 0.346 ± 0.148 in HSN, and 0.300 ± 0.067 in the CG; AASI was significantly (p = 0.009) higher in IgAN vs. CG. PP was higher (P = 0.04) in IgAN vs. HSN. Based on ABPM data, poorly-controlled hypertension was found in 14 of 22 patients (63.6%) with previously diagnosed hypertension. No differences in BPV or nocturnal BP dip were found between the groups. In all children with IgAN/HSN, 24hDBP correlated significantly with proteinuria, cholesterol, triglycerides, and prednisone dose; BMI Z-score correlated with SBPV, DBPV, and PP. CONCLUSIONS: 1. Children with IgAN have higher arterial stiffness compared to healthy peers. 2. In children with IgAN/HSN, proteinuria and hyperlipidemia are risk factors for elevated diastolic blood pressure, while obesity is a risk factor for increased blood pressure variability and pulse pressure. 3. Pediatric patients with IgAN/HSN require regular ABPM evaluation to allow for early detection of poor pharmacological control of hypertension.
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Renalase in Children with Glomerular Kidney Diseases.

Studies suggest that renalase, a renal catecholamine-inactivating enzyme, plays a major role in the pathogenesis of kidney and cardiovascular diseases in adults. This study seeks to determine the role of renalase in children with glomerular kidney diseases. We evaluated the serum renalase, arterial stiffness, intima-media thickness, blood pressure, and clinical and biochemical parameters in 78 children (11.9 ± 4.6 years of age) with glomerulopathies such as idiopathic nephrotic syndrome (40 cases), IgA nephropathy (12 cases), Henoch-Schönlein nephropathy (12 cases), and other glomerulopathies (14 cases). The control group consisted of 38 healthy children aged 11.8 ± 3.3 years. The mean renalase was 25.74 ± 8.94 µg/mL in the glomerulopathy group, which was not significantly different from the 27.22 ± 5.15 in the control group. The renalase level did not differ among various glomerulopathies either. However, proteinuric patients had a higher renalase level than those without proteinuria (28.43 ± 11.71 vs. 24.05 ± 6.23, respectively; p = 0.03). In proteinuric patients, renalase correlated with daily proteinuria. In the entire glomerulopathy group, renalase correlated with age, systolic central blood pressure (BP), diastolic peripheral and central BP, mean peripheral and central BP; peripheral diastolic BP Z-score, glomerular filtration rate, cholesterol, triglycerides, and pulse wave velocity. We conclude that in children with glomerulopathies renalase, although basically not enhanced, may underlie blood pressure elevation and arterial damage.

Enzymatic Activity of Candida spp. from Oral Cavity and Urine in Children with Nephrotic Syndrome.

Oral colonization with Candida spp. is not synonymous with a systemic active infection. The aim of the study was to evaluate enzymatic activity of Candida strains isolated from the oral cavity in patients with nephrotic syndrome (NS) and to compare it with the activity determined in urine. We studied 32 children with NS and 26 control healthy children. Children with NS were treated with glucocorticosteroids, cyclosporin A, mycophenolate mofetil or azathioprine. In all children, API-ZYM enzymatic tests were performed to evaluate hydrolytic enzymes of Candida isolated from the oral cavity and in urine. Candida spp. were isolated from the oral cavity in 11 patients with NS (34.4%), all receiving immunosuppressive treatment. All strains produced valine arylamidase, 9 alpha-glucosidase (E16), and 9 N-acetyl-beta-glucosaminidase (E18). A positive correlation between the presence of Candida in the oral cavity and E16 and E18 enzymatic activity in both oral cavity and urine was found. A dose of cyclosporin A had an effect on the enzymatic activity (p < 0.05). We conclude that immunosuppressive treatment of NS in children may predispose to systemic Candida invasion. The results of this study suggest that oral candida infection should be monitored in children with nephrotic syndrome, particularly those treated with immunosuppressive agents.

Usefulness of urinary collagen IV excretion for predicting the severity of Henoch-Schönlein nephropathy children.

THE AIM OF THE STUDY: The aim of the study was to evaluate the usefulness of urinary collagen IV (Col IV) excretion for predicting the severity of autoimmune renal inflammation in children with HSN (Henoch-Schönlein nephritis). MATERIAL AND METHODS: We studied 26 children, in whom HSN was diagnosed based on kidney biopsy. In all patients, urinalysis was performed and 24-hour urinary protein excretion was measured at the onset of the disease. All kidney biopsies were also scored using the Oxford classification: M - mesangial hypercellularity score (M0 absent, M1 present); E - presence of endocapillary proliferation (E0 absent, E1 present), S - segmental glomerulosclerosis/adhesion (S0 absent, S1 present), T - tubular atrophy/interstitial fibrosis (T0 ≤ 25%, T1 26-50%, T2 > 50%). The MEST score was calculated as the sum of M + E + S + T. RESULTS: Urinary Col IV level was significantly higher in the study group than in control group. Urinary Col IV level was insignificantly higher in group A (nephrotic proteinuria) compared to the B (non-nephrotic proteinuria) and C (without proteinuria).We found no significant differences in the age at the disease onset, severity of proteinuria, and Col IV between groups 1 (S0, T0) and 2.(S1,T1/T2). The MEST score was significantly higher in group 2 than group 1. CONCLUSIONS: Urinary Col IV excretion in children with HSN may be related to the lesions severity by the Oxford classification but seems to be associated with the mean value (the MEST score). In younger children, a more aggressive disease course is observed, and thus earlier and more aggressive treatment should be considered in this group.

Treatment Outcomes in Children with Henoch-Schönlein Nephritis.

The aim of the present study was to quantify the effects of treatment of children with Henoch-Schönlein nephritis (HSN) evaluated on the basis of kidney biopsy findings. Data were analyzed from 32 patients with HSN (mean age 9.3 ± 3.5 years, 19 with nephrotic syndrome/nephrotic proteinuria NS/NP, 13 with nephritic syndrome NphS), in whom the diagnosis was confirmed by kidney biopsy. Patients received immunosuppressive treatment (azathioprine or cyclophosphamide) and/or steroids and renoprotection according to a defined protocol. Patients were referred to a specific treatment protocol selected on the basis of clinical symptoms of nephropathy (NS/NP or NphS) and histopathological grade according to the WHO classification. Grade I-II changes were defined as mild HSN, and grade III-V WHO as severe HSN. The follow-up kidney biopsy was performed upon obtaining parental consent in 17 children. Following treatment, proteinuria resolved in 78 % children with mild HSN and 87 % children with severe HSN. In kidney biopsy, histological improvement was seen in 59 % children and no worsening in 35 %. We conclude that a flexible treatment protocol related to clinical symptoms and histological staging may contribute to a reduction of proteinuria and a delay in disease progression in children with HSN.