Nephrotic syndrome in children and new treatment recommendations

Nefrotski sindrom (NS) je je najčešća glomerulska bolest u dječjoj dobi, iako je njegova incidencija 2–7/100 000 djece na godinu. NS se može podijeliti prema dobi pojavljivanja, mogućem pojavljivanju u članova obitelji, mogućem pojavljivanju u sklopu sindroma, prema tome da li zahvaća samo bubreg ili nastaje u sklopu neke bolesti. Prema patohistološkom nalazu NS također može biti podijeljen na bolest minimalnih promjena, fokalnu segmentalnu glomerulosklerozu, difuznu mezangijsku proliferaciju i IgM nefropatiju. U ovom radu analiziramo aktualne smjernice o vođenju i liječenju djece s NS.Nephrotic syndrome (NS) is the most frequent glomerular disease in the childhood with incidence of 2–7/100000 children/year. NS can be divided regarding the age of occurence, possible familiar appearance, whether it is a part of certain syndrome or comes alone, whether it affects the kidney only or it apears together with other diseases. According the pathohistological characteristics, NS can be divided in minimal change disease, focal segmental glomerulosclerosis, difusse mesangial sclerosis, and IgM nephropathy. In this article we discuss actual guidelines for the management and therapy of NS

THE CHARACTERISTICS OF THE URINARY BLADDER WALL IN INFANTS DURING THE FIRST 6 MONTHS OF

Cilj: Odrediti ultrazvukom normalne vrijednosti debljine stijenke mokraćnog mjehura zdrave dojenčadi u prvih 6 mjeseci života i utvrditi postoje li razlike s obzirom na spol. Ispitanici i metode: Obavljen je ultrazvučni probir mokraćnog mjehura 416-ero zdrave donošene dojenčadi (216 muške i 200 ženske) u dobi od 0,5 do 6 mjeseci života. Debljine stijenke mokraćnog mjehura analizirane su ultrazvučnim aparatom Siemens Sonoline Prima, semikonveksnom sondom od 5,0 MHz i linearnom sondom od 7,5 MHz. Rezultati: Prosječna vrijednost debljine stijenke iznosila je 2,32 0,542 mm (95% indeks povjerenja: 2,27 – 2,37). Najmanja zabilježena debljina stijenke je bila 1 mm, a najveća 4 mm. Prosječna vrijednost debljine stijenke mokraćnog mjehura u muške dojenčadi iznosila je 2,42 0,56 mm, a prosječna vrijednost za žensku dojenčad iznosila je 2,21 0,50 mm. Studija je pokazala da postoji statistički značajna razlika u smislu nešto većih vrijednosti debljine stijenke mokraćnog mjehura u muške dojenčadi nego u ženske (t=3,97, p=0,00009, p0,01). Zaključak: Ovakvi bi se rezultati mogli očekivati jer mokraćni mjehur muškog djeteta mora proizvesti nešto veći tlak da bi izbacio urin kroz značajno dulju i užu uretru, nego mjehur ženskog djeteta. Takva relativna hiperfunkcija mokraćnog mjehura muškog dojenčeta rezultira relativnim zadebljanjem njegove stijenke, što pridonosi fiziološkoj različitosti među spolovima.Objectives: to determine by ultrasonograph the normal values of bladder wall thickness in healthy infants in the first 6 months of life and to observe the possible differences between sexes. Patients and Methods: Ultrasonograph screening was performed in 416 healthy term infants (216 males and 200 females) aged between 0.5 and 6 months. Bladder wall thicknesses were analyzed using a Sonoline Prima ultrasound machine with semi convex probe of 5.0 MHz, and linear probe of 7.5 MHz. Results: The mean bladder wall thickness was 2.32 0.542 mm (95% confidence interval: 2.27-2.37). The minimal bladder wall thickness was 1.0 mm, and maximal 4.0 mm, respectively. The average bladder wall thickness was 2.42 0.56 mm in males, and 2.21 0.50 mm in females. We found a statistically significant difference between bladder wall thickness of male and female infants in the first 6 months of life. The bladder wall in the male infants was thicker than in female infants (t=3.97, p=0.00009, p<0.01). Conclusion: These results might be expected because the male urinary bladder needs somewhat higher pressure to expel the urine via the significantly longer and narrower urethra than the bladder in female infants. That relative hyperfunction of the male bladder results in a relatively thicker bladder wall, what contributes to physiologic variances between sexes in infancy

Prirođene anomalije bubrega i urinarnog trakta (CAKUT)

Congenital anomalies of the kidney and urinary tract (CAKUT) are wide spectrum of prenatal malformations (isolated or as a part of syndromes), accounting for up to one quarter of overall birth defects and causes endstage renal disease in up to a half of these cases. The most sever CAKUT phenotypes arise from a disturbed differentiation or interaction of the ureteric bud and the metanephric mesenchyme. CAKUT can be triggered through interplay of various genetic and epigenetic factors, as well as by numerous extrinsic factors including maternal diabetes, medications, and folate and iron deficiency, highlighting environmental factors that modify expression of disease. Genetic impairments (about 40 monogenic isolated and about 150 as a part of a syndrome) underlay about 15% of cases with variable expressivity and incomplete penetrance. Copy number variations (CNVs) and submicroscopic chromosomal imbalances are diagnostic challenge. Early identification of mutations in genes which can lead to CAKUT can facilitate targeted therapy. Gene panels based on next generation sequencing technology (NGS) might elucidate and significantly improve the process of testing and may lead to proper and thereby more effective diagnosis of CAKUT.Kongenitalne anomalije bubrega i urinarnog trakta (CAKUT) predstavljaju širok spektar prenatalnih malformacija (izoliranih ili u sklopu sindroma), koje čine do jedne četvrtine ukupnih urođenih mana i uzrokuju završnu bubrežnu bolest u do polovice ovih slučajeva. Najteži CAKUT fenotipovi proizlaze iz poremećene diferencijacije ili interakcije mokraćovodnog pupoljka i metanefričkog mezenhima. CAKUT može nastati međudjelovanjem različitih genetskih i epigenetskih čimbenika, kao i zbog brojnih vanjskih čimbenika kao što su dijabetes majke, lijekovi, nedostatak folata i željeza, uz naglasak na čimbenike okoliša koji modificiraju ekspresiju bolesti. Genetski poremećaji (oko 40 izoliranih gena i oko 150 koji su dio sindroma) su u pozadini oko 15% slučajeva s promjenjivim izražajem i nepotpunom penetrantnosti. Varijacije broja kopija i submikroskopske kromosomske neravnoteže predstavljaju dijagnostički izazov. Rano prepoznavanje mutacija u genima koje mogu dovesti do CAKUT-a olakšali bi ciljanu terapiju. Paneli gena temeljeni na tehnologiji sekvenciranja sljedeće generacije mogli bi razjasniti i značajno poboljšati proces testiranja i dovesti do ispravne i učinkovitije dijagnoze CAKUT-a

EPIDEMIOLOŠKI PODATCI BUBREŽNIH BIOPSIJA U JUŽNOJ HRVATSKOJ – IZVJEŠTAJ O 22-GODIŠNJEM ISKUSTVU KBC-A SPLIT

The Croatian Registry of Native Renal Biopsy (CRNRB) was established in 2019. Thus, in this study, we present retrospective data on kidney biopsies in adult patients performed at the Split University Hospital Center from 1994 to 2019 before the CRNRB establishment. The aim of the study was to show epidemiological data on glomerular diseases in southern Croatia in order to compare them with others and provide data for the establishment of the CRNRB. During the study period, 110 patients (mean age 46.6±15.4, age range 17-76 years), 68 men and 42 women, underwent renal biopsy at the Department of Internal Medicine, Split University Hospital Center in Split. Data on age, sex, serum creatinine, urinalysis, daily proteinuria, and complications after biopsy were collected and related to indication for biopsy and pathological diagnosis. Light and immunofluorescence analysis was supplemented by electron microscopy in 63.5% of cases. Indications for biopsy were nephrotic syndrome (64.5%), asymptomatic urinary tract abnormalities (12.7%), and acute renal failure of unknown cause (9.1%). The most common diagnosis was IgA nephropathy (IgAN) (20.9%), the prevalence of which decreased during the study period. IgAN was followed by focal segmental glomerulosclerosis (FSGS) (19.1%), membranous nephropathy (13.6%), lupus nephritis and minimal change disease (8.2%), crescentic glomerulonephritis (5.4%), embranoproliferative glomerulonephritis (4.5%), mesangial proliferative glomerulonephritis (3.6%), amyloidosis (3.6%), Henoch-Schönlein nephritis (3.6%), and Alport syndrome (2.7%). Other forms of glomerular diseases were rarely found. IgAN was most frequently found in men (26.5%) and FSGS in women (21.4%). These data can be included in the historical epidemiological observation of glomerular diseases in Southeastern Europe. The guidelines for performing biopsies need to be constantly updated to improve preventive and therapeutic strategies.Hrvatski registar nativne bubrežne biopsije (CRNRB) uspostavljen je 2019. godine. Stoga u ovom istraživanju prikazujemo retrospektivne podatke biopsija bubrega odraslih bolesnika KBC-a Split obavljenih od 1994. do 2019. godine prije uspostave CRNRB-a. Cilj rada bio je prikazati epidemiološke podatke o glomerularnim bolestima u južnoj Hrvatskoj radi usporedbe s drugima i dobivanja podataka za uspostavu CRNRB-a. U promatranom razdoblju 110 bolesnika (raspon dobi 17-76 godina, srednja dob 46,6±15,4 godina), 68 muškaraca i 42 žene, bilo je podvrgnuto biopsiji bubrega na Klinici za unutarnje bolesti KBC-a Split. Podatci o dobi, spolu, kreatininu u serumu, analizi mokraće, dnevnoj proteinuriji i komplikacijama nakon biopsije prikupljeni su i povezani s indikacijom za biopsiju i patološkom dijagnozom. Analiza svjetlosnom mikroskopijom i imunofluorescencijom dopunjena je elektronskom mikroskopijom u 63,5 % slučajeva. Indikacije za biopsiju bile su nefrotski sindrom (64,5 %), asimptomatske abnormalnosti mokraćnog sustava (12,7 %) i akutno zatajenje bubrega nepoznatog uzroka (9,1 %). Najčešća dijagnoza bila je IgA nefropatija (IgAN) (20,9 %), učestalost koje se smanjila tijekom promatranog razdoblja. Nakon IgAN-a slijede žarišna segmentna glomeruloskleroza (FSGS) (19,1 %), membranska nefropatija (13,6 %), lupusni nefritis i bolest minimalnih promjena (8,2 %), polumjesečasti glomerulonefritis (5,4 %), membranoproliferativni glomerulonefritis (4,5 %), mezangijski proliferativni glomerulonefritis (3,6 %), amiloidoza (3,6 %), Henoch-Schönleinov nefritis (3,6 %) i Alportov sindrom (2,7 %). Drugi oblici glomerularnih bolesti rijetko su nađeni. IgAN je najčešće nađen u muškaraca (26,5 %), a FSGS u žena (21,4 %). Ti se podatci mogu uključiti u povijesno epidemiološko promatranje glomerularnih bolesti u jugoistočnoj Europi. Smjernice za izvođenje biopsije bubrega potrebno je stalno ažurirati kako bi se poboljšale preventivne i terapijske strategije

Prirođene anomalije bubrega i urinarnog trakta (CAKUT)

Congenital anomalies of the kidney and urinary tract (CAKUT) are wide spectrum of prenatal malformations (isolated or as a part of syndromes), accounting for up to one quarter of overall birth defects and causes endstage renal disease in up to a half of these cases. The most sever CAKUT phenotypes arise from a disturbed differentiation or interaction of the ureteric bud and the metanephric mesenchyme. CAKUT can be triggered through interplay of various genetic and epigenetic factors, as well as by numerous extrinsic factors including maternal diabetes, medications, and folate and iron deficiency, highlighting environmental factors that modify expression of disease. Genetic impairments (about 40 monogenic isolated and about 150 as a part of a syndrome) underlay about 15% of cases with variable expressivity and incomplete penetrance. Copy number variations (CNVs) and submicroscopic chromosomal imbalances are diagnostic challenge. Early identification of mutations in genes which can lead to CAKUT can facilitate targeted therapy. Gene panels based on next generation sequencing technology (NGS) might elucidate and significantly improve the process of testing and may lead to proper and thereby more effective diagnosis of CAKUT.Kongenitalne anomalije bubrega i urinarnog trakta (CAKUT) predstavljaju širok spektar prenatalnih malformacija (izoliranih ili u sklopu sindroma), koje čine do jedne četvrtine ukupnih urođenih mana i uzrokuju završnu bubrežnu bolest u do polovice ovih slučajeva. Najteži CAKUT fenotipovi proizlaze iz poremećene diferencijacije ili interakcije mokraćovodnog pupoljka i metanefričkog mezenhima. CAKUT može nastati međudjelovanjem različitih genetskih i epigenetskih čimbenika, kao i zbog brojnih vanjskih čimbenika kao što su dijabetes majke, lijekovi, nedostatak folata i željeza, uz naglasak na čimbenike okoliša koji modificiraju ekspresiju bolesti. Genetski poremećaji (oko 40 izoliranih gena i oko 150 koji su dio sindroma) su u pozadini oko 15% slučajeva s promjenjivim izražajem i nepotpunom penetrantnosti. Varijacije broja kopija i submikroskopske kromosomske neravnoteže predstavljaju dijagnostički izazov. Rano prepoznavanje mutacija u genima koje mogu dovesti do CAKUT-a olakšali bi ciljanu terapiju. Paneli gena temeljeni na tehnologiji sekvenciranja sljedeće generacije mogli bi razjasniti i značajno poboljšati proces testiranja i dovesti do ispravne i učinkovitije dijagnoze CAKUT-a

Changes in bacterial resistance patterns in children with urinary tract infections on antimicrobial prophylaxis at University Hospital in Split

Background: We assessed prevalence and resistance of uropathogens on antimicrobial agents (AA) from urine cultures (UC) in children hospitalized with urinary tract infections (UTI) at University Hospital in Split. Material/Methods: During the 7-year period, children hospitalized only once with UTI alone were compared to those repeatedly hospitalized, and who received long-term antimicrobial prophylaxis (LTAP), as well as those with associated anomalies of the urinary system (US). Results: E. coli was the most frequent isolate (67.7%) with resistance to ampicillin by 69.5%, amoxicillin/clavulonic acid by 3.5%, cephalexin by 6.6%, trimethoprim/sulfamethoxazole (TMP-SMX) by 27.5%, and nitrofurantoin by 0.4%. For other uropathogens, AA resistance rates were the following: 64.3%, 5.8%, 10.5%, 21.3%, and 7.9%. The high or increasing resistance to TMP-SMX is characterized by all uropathogens. Patients with anomalies of US showed a lower prevalence of E. coli and Enterococcus sp., but a higher prevalence of Pseudomonas sp., ESBL-producing E. coli and Klebsiella sp. than those without US anomalies. Repeatedly hospitalized patients showed a lower prevalence of E. coli, but a higher prevalence of Pseudomonas sp. and Klebsiella sp. than patients hospitalized only once. Both groups displayed significantly less resistance of Enterococcus sp. In patients receiving LTAP before hospitalization, E. coli was significantly more resistant to ampicillin, amoxicillin/clavulonic acid and TMP/SMX than in those without LTAP. Conclusions: Based on our results, we recommend excluding ampicillin altogether, and reconsideration of further use of TMP-SMX, as well as use of nitrofurantoin, cephalexin and amoxicillin/clavulonic acid for LTAP in our region

Schonlein-Henoch Syndrome in children and adolescents: epidemiologic data and coagulation disturbances

Svrha istraživanja bila je ispitati funkcionalnost trombocita u djece i adolescenata koji su bolovali od Schönlein-Henoch sindroma (SHS) u sklopu kojega se mogu pojaviti pojačana krvarenja, uz normalan broj trombocita, te prikazati epidemiološke podatke za istu populaciju. Najčešća mjesta manifestacije bolesti bila su koža i zglobovi. Bolest je bila najčešća u djece starosti između 7 i 20 godina, češća u djevojčica nego u dječaka. Najčešći poremećaj fiziološke aktivnosti trombocita bio je blokada otpuštanja endogenog ADP-a u slučaju kada je kao indukcijski agens bio upotrijebljen ADP. Štoviše, u 6 je pacijenata pokazana istovremena dezagregacija trombocita. Očito je da je pojačano krvarenje u sklopu SHS uzrokovano smanjenom funkcionalnom sposobnošću trombocita.The aim of the study was to examine the function of platelets in children and adolescents with Schönlein-Henoch Syndrome (SHS) presenting normal platelet count, and epidemiologic data. The most frequent SHS localization was the skin and joints. The most consistent defect in latelet aggregation was a block of the release of endogenous ADP when ADP was used as induction agent. In conclusion, our epidemiological data differ slightly from those observed by other authors. However, we have shown that increased tendency toward bleeding in SHS might be caused by function disturbances of platelets

Childhood-onset systemic lupus erythematosus in Croatia: demographic, clinical and laboratory features, and factors influencing time to diagnosis

OBJECTIVES Childhood-onset systemic lupus erythematosus (cSLE) presents with diverse clinical features and often with non-classical symptoms that may delay diagnosis and increase risk of morbidity and mortality. This paper aims to analyse incidence, and clinical and laboratory features of cSLE in Croatia between 1991 and 2010, and to identify factors influencing time to diagnosis. ----- RESULTS Medical records at three university-based tertiary care centres were analysed retrospectively for 81 children with cSLE (68 girls). Mean age at onset was 13.4±2.8 yr (interquartile range 3), and annual incidence varied from 1-15 per million at risk. The most frequent clinical and laboratory features were musculoskeletal symptoms (80%) and increased erythrocyte sedimentation rate (96%). The most frequent immunological laboratory findings were the presence of antibodies against histones (86%), double-stranded DNA (73%), and Sm protein (64%), as well as low levels of C3 complement (69%). Haematuria was present in 58% of children, proteinuria in 56%, and biopsy-confirmed lupus nephritis in 43%. Median time from symptom onset to diagnosis was 2 months (range 0-96). Time to diagnosis was inversely associated with ECLAM score (p<0.001), but it showed no association with age, gender, clinical features or distance from the nearest paediatric centre. ----- CONCLUSIONS This is the first large-scale, in-depth study of clinical and laboratory features of cSLE in Croatia. Among all demographic, laboratory and clinical features examined, ECLAM score alone was inversely associated with time to diagnosis. This highlights the need to improve detection of children with fewer symptoms early in the course of the disease, therefore serious consequences for prognosis could be avoided

C1Q NEPHROPATHY: CASE REPORTS AND LITERATURE REVIEW

C1q-nefropatija oblik je glomerulonefritisa definiran dominantnim nalazom C1q-imunosnih depozita u glomerulima. Bolest je rijetka. Najčešće se javlja u djece i mlađih odraslih. Klinički se najčešće očituje nefrotskim sindromom premda su opisani i drugi klinički sindromi kojima se ova bolest može manifestirati. Etiologija bolesti nije poznata, a patogeneza je najvjerojatnije imunosne prirode. Bolest je često rezistentna na glukokortikoide i druge imunosupresive i tada obično uzrokuje kronično zatajenje bubrega. U ovom radu prikazano je deset bolesnika s C1q-nefropatijom koja je potvrđena karakterističnim histološkim promjenama u tkivu bubrega koje je dobiveno biopsijom. Nijedan bolesnik nije imao kliničkih ni laboratorijskih nalaza karakterističnih za sistemski eritemski lupus. U svih su bolesnika komponente komplementa C3 i C4, kao i nalaz ANA, anti-dsDNA te ANCA-protutijela bili uredni.C1q nephropathy is considered a form of glomerulonephritis, defined by histological findings of dominant C1q immune deposits in renal biopsy. It is a rare disease, most often manifested in children and young adults. The most common clinical manifestation of the disease is nephrotic syndrome, but other renal syndromes could also be found. The cause of the disease is not known, but the immune pathogenesis could be assumed. Often, resistance to glucocorticoid or other immunosuppressive therapy is present, potentially leading to chronic renal insufficiency. We present ten patients with renal biopsy and clinical findings of C1q nephropathy. None of the patients had clinical or serological manifestations of systemic lupus. All patients had normal findings of C3 and C4 components of complement, as well as normal ANF, anti-dsDNA and ANCA antibodie

Pediatric Urolithiasis in Croatia

A retrospective review was performed of the records of 148 Croatian children with urolithiasis treated between 1989 and 2003. The study evaluated age, gender, family history, clinical symptoms, location of stone, laboratory findings, stone composition, mode of treatment and compared our results with data from higher and lower socio-economic countries. The mean age of our patients was 9.38 years (10 months to 18 years). Thirty-seven children (25%) were less than 5 years (group 1), 44 (29.7%) were between 5 and 10 years (group 2) and 67 (45.3%) were older than 10 years of age (group 3). There were 60 girls and 88 boys with overall male to female ratio of 1.47. Abdominal pain (83%) and haematuria (59.5%) were the main symptoms in the groups 2 and 3. Urinary tract infection was predominant symptom in the group 1 (62.1%). Calculi were located in the kidney in 90 children (60.8%), in the ureter in 39 (26.4%), in the bladder in 8 (5.4%). Urinary tract anomalies with or without infection were associate with a greater frequency of urolithiasis in the youngest age group and hypercalciuria was predominant cause in children over 5. Stone analysis was performed in 80 children. Predominant constituent of stones was calcium oxalate (48.7%), followed by struvite (25%), calcium phosphate (13.7%), cystine (10%) and uric acid (1.2%). Calcium oxalate stones were most common in all age groups. Struvite stones were most prevalent in the children younger than 5 years of age. Most patients (33.1%) underwent surgery for removal of their calculi. In 31.8% of children stones were passed spontaneously and the highest spontaneous passage rate was in the group 3 (37.3%). Stone composition, location and etiology in Croatian children are similar to those in developed Western countries