Inherited glomerulopathies of children: a Croatian experience

Bolesti iz spektra Alportovog sindroma (AS-a) nastaju kao posljedica mutacija gena za kolagen tip IV (COL43, COL4A4 i COL4A5). Spektar bolesti obuhvaća sve od tzv. benigne obiteljske hematurije na jednom kraju do klasičnog AS-a s ranom progresijom bolesti i izvanbubrežnim manifestacijama na drugom kraju spektra. Istraživačko iskustvo naše skupine počelo je 2003. godine, kada se prof. dr. sc. Danica Galešić Ljubanović vratila s edukacije iz nefropatologije od 18 mjeseci u Denveru, SAD i otvorila nefropatološki laboratorij u KB Dubrava. Dugogodišnji rad rezultirao je projektom Hrvatske zaklade za znanost ‘’Genotip-fenotip korelacija u AS-u i nefropatiji tankih glomerularnih bazalnih membrana (TBMN)’’ provedenom u periodu od 2015. do 2019. godine kojeg je profesorica bila voditelj. Glavni cilj istraživanja bio je utvrditi prevalenciju AS-a i TBMN-a u Hrvatskoj i razjasniti AS i TBMN histološki, genetski i klinički s krajnjim ciljem stvaranja registra pacijenta s ovim bolestima. Dijagnostički proces poremećaja iz spektra AS-a je često zahtijevan. Postoji velika varijabilnost u kliničkoj prezentaciji bolesti, ali i u histološkoj slici. Najtočniji test za otkrivanje uzročnih patogenih varijanti u genima kolagena tipa IV je opsežno paralelno genetsko testiranje čitavih kodirajućih sekvenci sva tri gena COL4A5, COL4A3 i COL4A4. Biopsija bubrega je od posebne koristi ako su klinički i podaci o članovima obitelji negativni i ne postoji mogućnost genetskog testiranja. Biopsija daje uvid u stupanj oštećenja parenhima bubrega te je u nekim slučajevima neizbježna dijagnostička metoda, osobito u pacijenata s neobičnim kliničkim tijekom bolesti (npr. neočekivano povećanje proteinurije). Tanke glomerularne bazalne membrane (GBM) su morfološki entitet utvrđen mjerenjem na elektronskoj mikroskopiji (EM) te su za razumijevanje njihovog značaja neophodni klinički i genetski podaci.Alport spectrum disorders are result of mutations in the type IV collagen genes (COL43, COL4A4 and COL4A5). The spectrum of diseases includes the so-called benign familial hematuria at one end to classic Alport syndrome (AS) with early progression and extrarenal manifestations at the other end of the spectrum. The research experience of our group started in 2003 when professor Danica Galešić Ljubanović returned to Zagreb after 18 months education in renal pathology (Denver, USA) and started a renal pathology laboratory at Dubrava University Hospital. This long-term work resulted in a project of the Croatian Science Foundation “Genotypephenotype correlations in Alport’s syndrome and thin glomerular basement membrane nephropathy” conducted in the period from 2015 to 2019 under the leadership of professor Galešić Ljubanović. The main goal of the study was to determine the prevalence of AS and thin glomerular basement membrane nephropathy (TBMN) in Croatia and to clarify AS and TBMN histologically, genetically and clinically with the ultimate goal of creating a registry of patients with AS and TBMN. The diagnostic process of AS spectrum disorders is often challenging. There is great variability in the clinical presentation of the disease, but also in the histological findings. The most accurate test for detecting causative pathogenic variants in type IV collagen genes is extensive parallel genetic testing of the entire coding sequences of all three COL4A5, COL4A3, and COL4A4 genes. A kidney biopsy is especially helpful if there are negative clinical and pedigree data and there is no possibility of genetic testing. The biopsy provides insight into the degree of kidney parenchymal injury and is in some cases an unavoidable diagnostic method, especially in patients with type IV collagen mutations with an unusual clinical course of the disease (such as an unexpected increase in proteinuria). Thin glomerular basement membranes are a morphological entity determined by measurement on electron microscopy, and clinical and genetic data are necessary to understand their significance

Marcel Kornfeld – Forgotten Pathologist and Respected Teacher

Autori su u radu prikazali život i rad Marcela Kornfelda (1886. – 1937.), patologa i sveučilišnog nastavnika. U radu je kronološki prikazan Kornfeldov život, od njegovih početaka u Donjoj Tuzli do njegove smrti u Zagrebu. Istaknuti su najvažniji detalji iz njegova života i bogate karijere koju je prekinula smrt u 51. godini života. Uz literaturu, pri nastanku rada veliku važnost su imali arhivski izvori pohranjeni na Medicinskom fakultetu Sveučilišta u Zagrebu i u Državnom arhivu u Zagrebu.The authors present the life and work of Marcel Kornfeld (1886 – 1937), a pathologist and a university teacher. The paper chronologically describes Kornfeld’s life, from his beginnings in Donja Tuzla to his death in Zagreb. The most important details from his life and rich career, which was interrupted by his death at the age of 51, are highlighted. The paper was written based on extensive literature and archival research

The Banff classification of renal allograft pathology

Do ranih 1990-ih nije postojala standardizirana međunarodna klasifikacija biopsija bubrežnih presadaka. To je rezultiralo značajnom heterogenošću patohistoloških nalaza između različitih centara. Skupina nefropatologa, nefrologa i transplantacijskih kirurga napravila je u Banffu (Alberta, Kanada) 1991. prvi klasifikacijski sustav histoloških promjena u transplantiranom bubregu koji je pružio smjernice za patohistološku i kliničku dijagnozu te omogućio usporedbu između istraživačkih i kliničkih studija za dijagnozu, liječenje i ishod transplantiranih bubrega. Bio je to početak danas općeprihvaćene Banff klasifikacije. Navedeni eksperti nastavili su se sastajati svakih nekoliko godina te su Banff klasifikaciju prilagođavali i mijenjali u skladu s najnovijim spoznajama. Cilj rada je prikazati Banff klasifikaciju bubrežnih presadaka kroz njenu povijest od početaka do posljednjeg izvještaja. Dijagnostička procjena patologije bubrežnih presadaka uvelike je poboljšana, kvantificirana i klinički dokazana, ali mnoga pitanja još treba proučiti. Trenutne preporuke se i dalje klinički vrednuju, a izvještaj o tome i nove teme bit će raspravljeni na jubilarnom sastanku o tridesetoj godišnjici Banff susreta 2021. godine u gradu Banffu iz kojega je klasifikacija i potekla.Until the early 1990s, there was no standardized international classification of the renal allograft biopsies resulting in significant heterogeneity of biopsy findings between different centres. A group of nephropathologists, nephrologists and surgeons developed in Banff (Alberta, Canada) in 1991 the first classification system (the so-called Banff classification) which provided guidelines for the pathohistological and clinical diagnosis and enabled meaningful comparisons between research and clinical studies for diagnosis, treatment and outcome of the renal allograft pathology. The aim of this article is to present the Banff classification through its history from the beginnings to the recent reports. The diagnostic assessment of the kidney allograft pathology has been greatly improved, quantified, and clinically proven but many issues remain to be studied. Current recommendations are further clinically validated and the report and new topics will be discussed at the jubilee meeting in 2021 in Banff, the city from which the Banff classification originates

Tiopronin i/ili NSAR? Nefrotski sindrom i akutni intersticijski nefritis u mlade žene s cistinurijom - prikaz slučaja

Cystinuria is an autosomal recessive disease that leads to recurrent stone formation. Tiopronin, a glycine derivative with a free thiol similar to penicillamine, prevents stone formation and facilitates their dissolution. Nephrotic-range proteinuria is a serious and relatively uncommon adverse effect, reported in 6-10% of patients, most frequently during the first year of tiopronin use. Various patterns of morphologic kidney injury have been associated with tiopronin use, including MCD, MN, and MPGN. Acute interstitial nephritis can be caused virtually by any drug. Non-steroidal anti-inflammatory drugs (NSAID s) may cause AIN , with or without nephrotic syndrome due to minimal change disease or membranous nephropathy.Cistinurija je autosomno recesivna bolest koja dovodi do recidivirajućeg stvaranja kamenaca. Tiopronin, derivat glicina sa slobodnim tiolom, sličan penicilaminu, sprječava stvaranje kamenaca i čini ih topljivima. Proteinurija nefrotskog raspona ozbiljan je i relativno rijedak neželjeni učinak, zabilježen u 6-10% bolesnika, najčešće tijekom prve godine upotrebe tiopronina. Razni obrasci morfološke ozljede bubrega povezani su s upotrebom tiopronina, uključujući MCD, MN i MPGN. Akutni intersticijski nefritis može biti uzrokovan gotovo bilo kojim lijekom. Nesteroidni protuupalni lijekovi (NSAR) mogu uzrokovati AIN , s nefrotskim sindormom ili bez njega uzrokovanog bolešću minimalnih promjena ili membranskom nefropatijom

DRUG INDUCED ALLERGIC INTERSTITIAL NEPHRITIS

Alergijski intersticijski nefritis (AIN) uzrokovan lijekovima rijedak je oblik bubrežne bolesti koji se klinički primarno manifestira akutnom bubrežnom insuficijencijom. Najčešća etiopatogeneza AIN-a reakcija je preosjetljivosti na lijekove među kojima su najzastupljeniji antibiotici. Najvažnija dijagnostička metoda u bolesnika sa sumnjom na AIN jest biopsija bubrega. Uz ukidanje uzročnog lijeka, u liječenju AIN preporučuje se primjena glukokortikoida, u dozi od 1 mg/kg/dan s postepenim snižavanjem doze, u trajanju do 3 mjeseca. U ovom radu, prikazali smo 10 bolesnika kod kojih je nakon pregleda bubrežnog bioptata s nalazom AIN-a, retrospektivno učinjena analiza kliničkih i biokemijskih podataka. Definirane su četiri različite uzročne skupine lijekova AIN-a, a najčešći su bili antibiotici. U kliničkoj prezentaciji dominirala je akutna bubrežna insuficijencija s medijanom serumskog kreatinina od 497,5 µmol/L. Svi bolesnici osim jednoga liječeni su preporučenim dozama glukokortikoida. Troje bolesnika liječeno je i hemodijalizom. U svih bolesnika došlo je do oporavka bubrežne funkcije, uz medijan serumskog kreatinina nakon tromjesečnoga glukokortikoidnog liječenja (u sedmero bolesnika) od 152 µmol/L (p=0,018).The allergic interstitial nephritis (AIN) is a rare renal disorder which is commonly clinically presented with an acute renal failure. AIN is the most frequent result of the hypersensitivity related to drugs (most often antibiotics). In the patients with clinical suspicion to a drug related AIN, kidney biopsy is the most important diagnostic procedure. Except of causative drug discontinuation, AIN therapy is based on high dose glucocorticoids 1 mg/kg/day with dose tapering during consecutive 3 months. In the present work, we have shown 10 patients with drug induced AIN. We identified 4 causative drug groups among which most frequent were antibiotics. In clinical presentation of our patients acute renal failure was dominant and median of baseline serum creatinine was 497.5 µmol/L. In all patients the kidney biopsy was performed and nine patients (90%) have been treated with recommended glucocorticoid regimen, additionally, in 3 patients hemodialysis was introduced. In all patients, reduction in serum creatinine value was achieved with serum creatinine median of 152 µmol/L after a three-month glucocorticoid treatment (p=0.018)

Goodpastureov sindrom – prikazi bolesnika [Goodpasture's syndrome - case reports]

Goodpasture's syndrome is a rare clinical entity characterized by rapidly progressive glomerulonephritis, diffuse pulmonary hemorrhage and the presence of circulating autoantibodies to the glomerular basement membrane (GBM). Autoantibodies bind to reactive epitopes of noncollagenous domain of the collagen type IV alpha-3 chain in glomerular and alveolar basement membranes. Autoantibodies activate the complement cascade resulting in tissue injury by the type II hypersensitivity reaction according to the Coombs and Gell classification of antigen-antibody reactions. Prognostic factors include the renal excretory function and the degree of renal and lung damage at the time of presentation. Prompt diagnosis and early and adequate medical treatment is vital for patients. Clinical treatment must be aggressive in order of achieving better outcome. This article describes three patients who clinically presented with renopulmonary syndrome, renal failure, hematuria, proteinuria and hemoptysis. Kidney biopsy diagnosis was crescentic glomerulonephritis due to antibodies against GBM. In all three patients we started therapy with glucocorticoids and cyclophosphamide combined with plasma exchange therapy. In two patients who initially had severe impairment of renal function and high percentage of crescents in the renal biopsy, kidney function recovery was not achieved. In one patient, who at the time of clinical presentation showed milder renal failure and lower percentage of crescents in renal biopsy, the full recovery of renal function was obtained

GOODPASTURE’S SYNDROME – CASE REPORTS

Goodpastureov sindrom rijedak je klinički entitet karakteriziran brzoprogresivnim glomerulonefritisom (BPGN), difuznim plućnim hemoragijama i prisutnošću cirkulirajućih autoprotutijela na glomerularnu bazalnu membranu (GBM). Autoprotutijela se vežu na reaktivne epitope nekolagene domene a-3 lanca kolagena tipa IV, sastavnog dijela alveolarne i glomerularne bazalne membrane, te aktiviraju kaskadu komplementa, što rezultira oštećenjem tkiva po tipu II reakcije preosjetljivosti prema Coombsu i Gellu. Prognostički faktori uključuju patohistološke promjene i promjene ekskrecijske funkcije bubrega te stupanj plućnog oštećenja u trenutku očitovanja bolesti. Brzo postavljena dijagnoza i što ranije provedeno adekvatno liječenje osobito su važni za bolesnike. Agresivno liječenje kombinacijom imunosupresivne terapije i plazmafereze ima najbolje izglede za uspjeh. U ovom radu prikazano je troje bolesnika koji su se klinički očitovali renopulmonalnim sindromom: bubrežnim zatajenjem, hematurijom, proteinurijom i hemoptizama. Histološki u tkivu bubrega dobivenom biopsijom u svih bolesnika radilo se o glomerulonefritisu s polumjesecima uzrokovanom protutijelima na GBM. U sve troje bolesnika provedeno je liječenje glukokortikoidima, ciklofosfamidom i plazmaferezom. Svi bolesnici preživjeli su uz remisiju plućne bolesti. U dva bolesnika koja su u trenutku kliničke prezentacije imala znatno sniženu ekskrecijsku bubrežnu funkciju i visok postotak polumjeseca u tkivu bubrega dobivenog biopsijom došlo je do trajnoga gubitka bubrežne funkcije. U jednog bolesnika koji je u trenutku očitovanja bolesti pokazivao lakše bubrežno oštećenje te manji postotak polumjeseca došlo je do potpunog oporavka bubrežne funkcije.Goodpasture’s syndrome is a rare clinical entity characterized by rapidly progressive glomerulonephritis, diffuse pulmonary hemorrhage and the presence of circulating autoantibodies to the glomerular basement membrane (GBM). Autoantibodies bind to reactive epitopes of noncollagenous domain of the collagen type IV a-3 chain in glomerular and alveolar basement membranes. Autoantibodies activate the complement cascade resulting in tissue injury by the type II hypersensitivity reaction according to the Coombs and Gell classification of antigen-antibody reactions. Prognostic factors include the renal excretory function and the degree of renal and lung damage at the time of presentation. Prompt diagnosis and early and adequate medical treatment is vital for patients. Clinical treatment must be aggressive in order of achieving better outcome. This article describes three patients who clinically presented with renopulmonary syndrome, renal failure, hematuria, proteinuria and hemoptysis. Kidney biopsy diagnosis was crescentic glomerulonephritis due to antibodies against GBM. In all three patients we started therapy with glucocorticoids and cyclophosphamide combined with plasma exchange therapy. In two patients who initially had severe impairment of renal function and high percentage of crescents in the renal biopsy, kidney function recovery was not achieved. In one patient, who at the time of clinical presentation showed milder renal failure and lower percentage of crescents in renal biopsy, the full recovery of renal function was obtaine