Pedijatrijski nefrotski sindrom: međusobna interakcija oksidativnog stresa i inflamacije

Background: The pathophysiological mechanisms crucial in the development of nephrotic syndrome (NS) in the pediatric population are still not fully understood. This study aimed to investigate the relationship between hypertension, oxidative stress, and inflammation in pediatric patients during the acute phase of the disease. Methods: The study included 33 children, aged 2 to 9 years, with nephrotic syndrome. Blood samples were collected during the acute phase and remission. Parameters of oxidative status were determined, including total oxidative status (TOS), advanced oxidation protein products (AOPP), prooxidant-antioxidant balance (PAB), sulfhydryl groups (- SH), paraoxonase 1 (PON1), and total antioxidant status (TAS) in serum, measured spectrophotometrically. Inflam- matory parameters such as pentraxin 3 (PTX3), leptin, programmed cell death ligand 1 (PD-L1), and E-cadherin were determined using enzyme-linked immunosorbent assay (ELISA). Results: Patients with nephrotic syndrome and hypertension had significantly higher levels of advanced oxidation protein products and total antioxidant status (p=0.029 and p=0.003, respectively). During the acute phase of the dis- ease, lower activity of sulfhydryl groups and paraoxonase 1 was observed compared to remission (p<0.001, for both). Pentraxin 3 levels were higher, while leptin levels were lower during the acute phase (p<0.001, for both). Pentraxin 3 correlated with advanced oxidation protein products and total antioxidant status during the acute phase but not in remission (r s =0.42, p=0.027 and r s =0.43, p=0.025, respectively). A negative correlation between Advanced oxidation protein products and leptin was observed during the acute phase, which disappeared in remission (rs=-0.42, p=0.028). Conclusions: Results of this study show that hypertension influences oxidative stress markers, and decreased antioxi- dant capacity may contribute to nephrotic syndrome devel- opment. Pentraxin 3 appears as a potential disease activity marker, indicating a dynamic connection between inflam- mation and oxidative stress. Leptin may also play a role in oxidative stress in nephrotic syndrome.Uvod: Patofiziološki mehanizmi ključni u razvoju nefrotskog sindroma (NS) u pedijatrijskoj populaciji još uvek nisu u potpunosti razjašnjeni. Ova studija ima za cilj proučavanje sinergističkog delovanja oksidativnog stresa i inflamacije u patogenezi NS. Takođe, jedan od ciljeva ove studije je i ispitivanje veze hipertenzije sa stepenom oksidativnog stresa i inflama - cije kod pacijenata u akutnoj fazi bolesti. Metode: U studiju je uključeno 33 dece sa NS uzrasta od 2 do 9 godina. Uzorci krvi su prikupljeni tokom akutne faze i remisije. Od parametara oksidativnog statusa određivani su: totalni oksidativni status (TOS), uznapredovali proizvodi oksidacije proteina (AOPP), balans prooksidans-antioksidans (PAB), sulfhidrilne grupe (-SH), paraoksonaza 1 (PON1) i ukupan antioksidativni status (TAS) u serumu su mereni spektrofometrijski, a od parametara inflamacije su pentraksin 3 (PTX3), leptin, ligand programirane smrti ćelije 1 (PD-L1) i E-kadherin određivani metodom enzimskog imunosorbentnog testa (ELISA). Rezultati: Pacijenti sa NS i hipertenzijom imali su značajno više nivoe AOPP i TOS (p=0.029 i p=0.003, respektivno). U akutnoj fazi bolesti su uočene nižu aktivnost -SH i PON1 u poređenju sa remisijom (p<0.001, za oba). Nivoi PTX 3 su bili viši, dok su nivoi leptina bili niži tokom akutne faze (p<0.001, za oba). PTX 3 je korelirao sa AOPP i TAS u akutnoj fazi, ali ne i u remisiji (rs=0.42, p=0.027 i rs=0.43, p=0.025,respektivno). U akutnooj fazi utvrđena je negativna korelacija između AOPP i leptina, koja je nestala u remisiji (rs=-0.42, p=0.028). Zaključak: Rezultati ove studije ukazuju da hipertenzija utiče na markere oksidativnog stresa, a smanjeni antioksidativni kapacitet može doprineti razvoju NS. PTX3 se pojavljuje kao potencijalni marker aktivnosti bolesti, što ukazuje na dinamičku vezu između inflamacije i oksidativnog stresa. Leptin može igrati ulogu u oksidativnom stresu u NS

Associations of Apgar score and size at birth with lipoprotein subclasses in juvenile obesity

N Background/aim: Juvenile obesity is associated with several metabolic abnormalities, one of them being atherogenic dyslipidemia. Suboptimal fetal growth is associated with obesity risk in childhood, but also with increased rate of metabolic diseases in later life. This study investigated associations of neonatal data (Apgar score, birth weight and birth length) with low-density lipoprotein and high-density lipoprotein (LDL and HDL) subclasses in a group of obese children, as well as a possible impact of breastfeeding duration on obesity-associated lipoprotein subclasses distributions. Materials and methods: We included 42 obese children, aged 14.2 +/- 2.1 years. LDL and HDL subfractions were separated by gradient gel electrophoresis and biochemical parameters were assessed by routine methods. Results: Compared with obese children with Apgar >= 9, the group with Apgar lt 9 had significantly higher percentages of small, dense LDL particles (P lt 0.05), due to reduced LDL I (P lt 0.01) and increased LDL III subclasses (P lt 0.05). Birth weight was positively associated with the proportions of LDL I particles (P lt 0.001), whereas birth height positively correlated with the amount of HDL 2b subclasses (P lt 0.05). The group of never or less than 3 months breastfed children had significantly smaller LDL size (P lt 0.01) and lower proportion of HDL 2a particles (P lt 0.05) than their >= 3 months breastfed peers. Conclusion: The results showed significant associations of neonatal characteristics with LDL and HDL particle distributions in obese children. In addition, our results point toward positive aspects of longer breastfeeding duration on lipoprotein particle distributions in obese children

Rezistin, inflamacija i dislipidemija kod gojazne dece i adolescenata

Introduction: Childhood obesity is related to cardiovascular diseases and diabetes mellitus type 2 in later life. Resistin, an adipokine primarily secreted by monocytes and tissue macrophages in humans, is considered to be associated with these conditions. The Aim: To examine the correlations between resistin concentration and anthropometric parameters, lipid status, inflammatory markers and parameters of insulin resistance in obese children and adolescents. Material and Methods: The study included 66 patients (40 boys, 26 girls), which underwent anthropometric measuring and laboratory testing (glucose level, total cholesterol, high-density lipoprotein cholesterol (HDL-cholesterol), low-density lipoprotein cholesterol (LDL-cholesterol), triglycerides, uric acid, high-sensitivity C-reactive protein (hsCRP) and glycosylated hemoglobin (HbA1c). Insulin resistance was estimated with HOMA-IR (homeostasis model assessment of insulin resistance). Results: We determined that 63.3% of our patients had dyslipidemia, while hsCRP and uric acid levels suggested an ongoing inflammation. We established that there was a correlation between resistin concentration and waist to hip ratio (WHR) (r=0.294, p lt 0.05), as well as between resistin concentration and HOMA-IR (r=0.293, p lt 0.05). Also, uric acid levels correlated with obesity parameters. While comparing parameters by gender we found a significant difference in height (p lt 0.01), WHR (p lt 0.001), uric acid levels (p lt 0.01) and HOMA-IR (p lt 0.01). Conclusion: Our results show a link between obesity, inflammation and dyslipidemia in children and adolescents. In the future, resistin could become a significant clinical marker for evaluation of cardiometabolic risk.Uvod: Gojaznost u dečjem uzrastu se povezuje sa razvojem kardiovaskularnih bolesti i tipa 2 dijabetes melitusa u kasnijem dobu. Smatra se da je rezistin, adipokin kojeg u humanom organizumu luče monociti i tkivne makrofage, povezan sa ovim poremećajima. Cilj: Ispitati povezanost koncentracije rezistina kod gojazne dece i adolescenata sa antropometrijskim parametrima gojaznosti, lipidnim statusom, inflamatornim markerima i parametrima insulinske rezistencije. Materijal i metode: U istraživanju je učestvovalo 66 ispitanika (40 dečaka, 26 devojčica) kojima su izvršena antropometrijska merenja i laboratorijska ispitivanja (koncentracije glukoze, ukupnog holesterola, holesterola u česticama lipoproteina visoke gustine (eng. high-density lipoprotein, HDL) i niske gustine (eng. low-density lipoprotein, LDL), triglicerida, mokraćne kiseline, visokoosetljivog C-reaktivnog proteina (high-sensitivity C-reactive protein; hsCRP) i glikoziliranog hemoglobina (HbA1c)). Insulinska rezistencija je procenjena na osnovu modela za izračunavanje indeksa insulinske rezistencije (eng. homeostasis model assessment of insulin resistance; HOMA-IR). Rezultati: Kod 63,3% ispitanika utvrdili smo prisutnu dislipidemiju, a dobijene vrednosti hsCRP i mokraćne kiseline ukazuju na prisustvo inflamacije. Utvrdili smo korelaciju između koncentracije rezistina i odnosa obima struka i kukova (r=0,294, p lt 0,05) i između koncentracije rezistina i HOMA-IR (r=0,293, p lt 0,05). Ustanovili smo povezanost koncentracije mokraćne kiseline i parametara gojaznosti. Upoređivanjem parametara između polova, značajna razlika postoji u telesnoj visini (p lt 0,01), odnosu obima struka i kukova (p lt 0,001), mokraćnoj kiselini (p lt 0,01) i HOMA-IR (p lt 0,01). Zaključak: Naši rezultati ukazuju na povezanost gojaznosti, inflamacije i dislipidemije kod dece i adolescenata. Rezistin bi u budućnosti mogao biti značajan za procenu kardiometaboličkog rizika u ovoj populaciji

Early childhood height-adjusted total kidney volume as a risk marker of kidney survival in ARPKD

Abstract Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450–1098) ml/m in Null/null, 403 (260–538) ml/m in Null/mis, 230 (169–357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150–267) ml/m in CKD stage 1, 472 (266–880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies

Development of the lower urinary tract and its functional disorders

A normal development of lower urinary tract function control evolves from involuntary bladder empting (incontinence) during infancy to daytime urinary continence, and finally a successful day and night continence that is generally achieved by the 5th to 7th year of age. This gradual process primarily depends on the progressive maturation of the neural control of the lower urinary tract, but it is also influenced by behavioral training that evolves through social support. Functional voiding disorders (bladder dysfunction) are common problems during childhood. They are present in 5-15 % of general pediatric population, and in one-fifth of school-age children or in over one-third of patients of the pediatric urologist or nephrologist. More than half of children with bladder dysfunction have vesicoureteral reflux, and more than two-thirds have recurrent urinary tract infections. There is also a frequent association of bladder dysfunction with constipation and encopresis (dysfunctional elimination syndrome). Bladder dysfunction may cause a permanent damage to the upper urinary tract and kidneys. In addition, urinary incontinence, as the most common manifestation of bladder dysfunction can be the cause of major stress in schoolage children and have a negative effect on the child’s feeling of self-esteem. Thus, a timely detection and treatment of this group of disorders in children is highly significant

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis: The first four patients in Serbia

Introduction Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disease characterized by excessive renal magnesium and calcium wasting, bilateral nehrocalcinosis and progressive renal failure. This is the first report of FHHNC of four patients in Serbia. Outline of Cases The first three patients were siblings from the same family. The index case, a 9-yearold girl, presented with severe growth retardation, polyuria and polydipsia, while her brothers, 11 and 7 years old, were disclosed during family member screening. The father had a urolithiasis when aged 18 years, while intermittent microhaematuria and bilateral microlithiasis persisted later on. The fourth patient, a 16-year-old boy with sporadic FHHNC was discovered to have increased proteinuria at routine examination of urine before registration for secondary school. He was well grown up, normotensive, but had moderate renal failure (CKD 3 stage), mild hypomagnesaemia and severe hypercalciuria and nephrocalcinosis. Beside typical clinical and biochemical data, the diagnosis of FHHNC was confirmed by mutation analysis of the CLDN16 gene; in all four affected individuals a homozygous CLDN16 mutation (Leu151Phe) was found. Treatment with magnesium supplementation resulted in the normalization of serum magnesium levels only in one patient (patient 4), but hypercalciuria persisted and renal failure progressed in all patients. Conclusion FHHNC is a rare cause of chronic renal failure. The first four patients with FHHNC in Serbia have been here described. The diagnosis of FHNNC based on the findings of nephrocalcinosis with hypomagnesiaemia and hypercalciuria, was confirmed by homozygous paracellin1-mutation exhibiting a Leu151Phe.

Renal functional reserve in children with apparently normal congenital solitary functioning kidney

Objective: The aim of the study was to investigate renal functional reserve (RFR) and to assess its relationship with serum cystatin C and blood pressure in children with apparently normal congenital solitary functioning kidney (SFK). Material and methods: RFR was obtained from the difference of endogenous creatinine clearance (CrCs) before and after a meat-free oral protein load (OPL) in the patients who were pre-treated with cimetidine. Serum cystatin C and urinary protein excretion were determined before and after OPL Results: Among 22 patients (13 boys), aged 9.5 +/- 4.3years, 72.7% had increased serum cystatin C, and 54.5% had decreased RFR. Following OPL, CrCs and urine creatinine increased, while serum creatinine and cystatin C remained unchanged. The multiple regression analysis demonstrated that cystatin C could predict more than 90% of RFR variability. Conclusion: Half of the patients with apparently normal SFK had decreased RFR. Serum cystatin C is one of the best predictors of RFR

Proteinuria in frasier syndrome

Introduction. Frasier syndrome (FS) is a genetic form of glomerulopathy, which results from mutations in the Wilms’ tumour suppressor gene (WT1). Proteinuria in FS has been traditionally considered unresponsive to any medication and FS inevitably progresses to end stage renal failure. Case Outline. We present a patient with FS who had atypical clinical manifestation and unusual beneficial antiproteinuric response to renin-angiotensin system (RAS) inhibitors given in combination with indomethacin. After 13 years of follow-up, the patient is now 17-year old with normal renal functions and no proteinuria. Conclusion. RAS inhibitors combined with indomethacin showed beneficial effect in our patient. Thus, this combination might be the initial treatment of patients with FS. If this treatment strategy was not satisfied for at least 3 months, then CsA would be considered to be administered taking account of the nephrotoxicity and the increased risk of malignancy. Further prospective study is required to clarify this issue. [Projekat Ministarstva nauke Republike Srbije, br. OI175079

Hypercalciuria caused by CYP24A1 mutation: Fourteen years of the patient’s follow-up

Introduction. Recently, inactivation mutations of CYP24A1, the gene encoding vitamin D 24-hydroxylase, were identified in hypercalciuric nephrolithiasis and nephrocalcinosis. Here, we describe а long-term follow-up of a patient with hypercalciuric nephrolithiasis caused by CYP24A1 mutations. Case outline. A male Montenegro patient first presented with microhematuria at the age of five years. Hypercalciuria had been documented and for some time he had been treated by hydrochlorothiazide. After 12 years, the patient presented with macrohematuria and left-sided nephrolithiasis. He was found to have intermittent borderline hypercalcemia, suppressed parathyroid hormone, hypercalciuria, and increased plasma 25-hydroxy vitamin D [25(OH)D3]. The patient denied any vitamin D supplementation and all other causes of hypercalcemia were ruled out. Positive family history for nephrolithiasis (both parents and grandmother) and similar biochemical abnormalities detected in father and son pointed to an inherited disorder. A homozygous mutation in CYP24A1 (E143del) was found in the patient and his father, while mother is heterozygous. During the follow-up of two years, the patient underwent four extracorporeal shockwave lithotripsies, he was advised to increase water intake, and to avoid sunlight exposure. At the end of follow-up he was asymptomatic, and his renal ultrasound was normal, as well as his renal function, but hypercalciuria and low parathyroid hormone levels persisted. Conclusion. Hypervitaminosis D should be considered in children with idiopathic hypercalciuria, nephrolithiasis and nephrocalcinosis of unknown etiology. Recognition of CYP24A1 mutations in these patients may help to decrease the serious consequences by avoiding vitamin D supplements and excessive sun exposure. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 175079

Congenital nephrotic syndrome may respond to cyclosporine A: A case report and review of literature

Introduction. Congenital nephrotic syndrome (CNF) is manifested at birth or within the first three months of life. The Finnish-type of CNF is caused by the mutation of the NPHS1 gene, which encodes nephrin in the podocyte slit diaphragm. It is a very severe disease, for which immunosuppressive therapy is not advised. Here we describe a patient with CNF who responded to CsA by partial remission. Case outline. A girl aged 2.5 months presented with severe non-syndromic steroid-resistant nephrotic syndrome. She needed aggressive support including daily albumin infusions and diuretics. Substitution of vitamin D, thyroxin, and anticoagulants were regularly administered. She was also treated with angiotensin converting enzyme inhibitor, without clear benefits regarding proteinuria. In addition, she received intravenous gamma-globulin replacement therapy and antibiotics during frequent infections. While waiting for the results of genetic analyses and faced with many problems related to daily albumin infusions, infections, and thromboembolic complications, cyclosporine A (CsA) was introduced as an alternative to early nephrectomy and consequent renal failure. The patient responded by partial remission and CsA treatment continued at home without the albumin infusions. After almost five years since the beginning of the treatment, the patient’s renal function remains unreduced. Conclusion. Our case demonstrates that CsA can induce partial remission in patients with genetic forms of steroid-resistant nephrotic syndrome without influencing the glomerular filtration rate. However, its long-term effect and safety should carefully be monitored. [Project of the Ministry of Education, Science and Technological Development of Republic of Serbia, Grant No. 175079