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

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

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

Effects of Ramipril and Valsartan on Proteinuria and Renal Function in Patients with Nondiabetic Proteinuria

The renin-angiotensin system is involved in the progression of chronic renal disease of both diabetic and nondiabetic origin. The angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have been demonstrated to reduce urinary protein excretion and attenuate the development of renal injury. This prospective, randomized, 12-month study assessed the effects of ramipril (N=23) vs. valsartan (N=22) vs. combination of ramipril and valsartan (N=26) on proteinuria, renal function and metabolic profile in 71 patients with nondiabetic proteinuria with normal or slightly impaired renal function. Monotherapy with ramipril or valsartan and combination of these two drugs significantly reduced proteinuria, serum creatinine, cholesterol and triglycerides as well as systolic and diastolic arterial blood pressure. There was no significant difference among three study groups according to reduction of arterial blood pressure, serum cholesterol and triglycerides. At one year, a significant reduction in serum creatinine was recorded in all three study groups, whereas at 3 and 6 months a statistically significant reduction in serum creatinine was only observed in patients on combination therapy. In addition, at 3 months the reduction of proteinuria was significantly greater in patients on combination therapy than in those on either monotherapy. These results indicated the combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers to be more efficacious than either monotherapy in reducing proteinuria and serum creatinine level in the first 3 (proteinuria and serum creatinine) or 6 (serum creatinine) months of treatment

Effect of Unilateral Ureteral Obstruction and Anti-Angiotensin II Treatment on Renal Tubule Cell Apoptosis and Interstitial Fibrosis in Rats

Unilateral ureteral obstruction (UUO) results in a number of pathophysiological and morphological changes in the renal parenchyma, including interstitial inflammation and fibrosis, apoptotic changes of tubular and interstitial cells. Recent studies have indicated an association between renin-angiotensin system and apoptotic alterations in the kidney after unilateral obstructive nephropathy. In this study, the effect of ACE inhibitors and AT1 receptor antagonists on tubular cell apoptosis and interstitial fibrosis in obstructive nephropathy after UUO in rats was investigated. The study was conducted on Wistar rats with unilaterally ligated ureter and sham operated animals (control group). The rats with UUO were treated with ACE inhibitor (cilazapril) or AT1 receptor antagonists (losartan) and control group was treated with H2O. Sham-operated animals were treated in the same way. Tubular and interstitial cell apoptosis was detected morphologically by hematoxylin and eosin (HE) staining and terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL). The area of intersitial fibrosis was determined using computer-assisted image processing after Gomory silver impregnation of paraffin sections. All experimental animal groups with unilateral ureter ligation showed a significantly increased number of apoptotic tubular and interstitial cells in the obstructed kidney compared with the contralateral, unobstructed kidney. Histomorphometric analysis of renal interstitial fibrotic changes in the groups of rats treated with losartan or water showed a statistically significant difference (p < 0.05) between the operated and sham-operated animals. In conclusion, following UUO there is a significantly increased number of apoptotic tubular cells and interstitial fibrosis in the ipsilateral kidney compared with the contralateral kidney. ACE inhibitors and AT1 receptor antagonists could not decrease the extent of renal cells apoptosis and interstitial fibrosis after UUO

Plućno krvarenje i glomerulonefritis s polumjesecima u pacijentu sa seropozitivnom antiglomerularnom bolesti bazne membrane i anti-neutrofilnim citoplazmičnim antitijelima

Anti-glomerular basement membrane (anti-GBM) disease is an acute and life-threatening systemic autoimmune disorder. The coexistence of circulating anti-neutrophil cytoplasmic antibodies (ANCA) and anti-GBM disease, the so-called double-positive disease (DPD), is exceptionally rare. We report a unique case of DPD manifesting as pulmonary-renal syndrome (PRS) in a 46-year-old woman who first presented with clinical and radiological suspicion of pneumonia. Chest computed tomography scan later revealed bilateral alveolar hemorrhage. Kidney biopsy showed necrotizing crescentic (100% glomeruli) glomerulonephritis. On immunofluorescence microscopy, glomeruli were global linear positive for IgG, confirming anti-GBM disease. Double positivity was detected for circulating anti-myeloperoxidase ANCA (p-ANCA) and anti-GBM antibodies. Acute renal failure evolved rapidly. Therapeutic plasma exchange (TPE) and hemodialysis (HD) were initiated early in combination with intravenous pulse corticosteroid therapy followed by oral methylprednisolone and cyclophosphamide. Pulmonary hemorrhage resolved, but renal function could not be preserved. The patient remains HD dependent. This case report highlights that pulmonary symptomatology may be the leading clinical presentation of PRS, with initially normal renal function at DPD onset. Early recognition and diagnosis are therefore crucial to timely clinical intervention. The role of prompt kidney biopsy and initiation of TPE and HD in PRS must not be underestimated.Bolest protiv glomerularne bazalne membrane (anti-GBM) je akutna i po život opasna sistemska autoimuna bolest. Pojava cirkulirajućih antitijela na citoplazmu granulocita (engl. anti-neutrophil cytoplasmic antibody, ANCA) u bolesnika sa anti-GBM glomerulonefritisom, tako zvana dvostruko pozitivna bolest (engl. double-positive disease, DPD), je vrlo rijetka. Prikazujemo 46 godišnju bolesnicu u koje je prvo klinički i radiološki postavljena sumnja na upalu pluća, a koja se kasnije manifestirala sa pulmo-renalnim sindromom (PRS) odnosno DPD. Kompjutorskom tomografijom pluća dokazano je alveolarno krvarenje. Biopsijom bubrega dokazan je nekrotizirajući glomerulonefritis (100 % glomerula). Imunoflorescencija je pokazala pozitivne linearne IgG depozite, što odgovara anti-GBM glomerulonefritisu. U bolesnice su dokazana antitijela na mijeloperoksidazu p-ANCA i antitijela na glomerularnu bazalnu membranu. Liječena je terapijskom izmjenom plazme (engl. therapeutic plasma exchange, TPE), hemodijalizom te kombinacijom parenteralne pulsne terapije kortikosteroidima, kasnije oralnom primjenom metilprednisolona i ciklofosfamida. Došlo je do regresije krvarenja u plućima ali se bubrežna funkcija nije oporavila, zbog čega smo nastavili s redovitim hemodijalizama. Ovaj prikaz bolesnice pokazuje kako u DPD, plućna simptomatologija može biti vodeći simptom PRS sa urednom bubrežnom funkcijom u početku. Rano prepoznavanja i dijagnoza su značajni za pravovremeni početak liječenja. Potrebno je naglasiti značaj rane biopsije bubrega, ranog početka TPE te po potrebi i nadomještanje bubrežne funkcije hemodijalizom

Diabetic Nephropathy with Focal Segmental Glomerulosclerosis

Udruženost dijabetične nefropatije s primarnim glomerulonefritisom rijetka je kod šećerne bolesti tip 1. Nekoliko izvješća pokazuje da se primarni glomerulonefritis može razviti na osnovi dijabetične nefropatije. Ovi glomerulonefritisi obuhvaćaju idiopatski membranski glomerulonefritis, IgA glomerulonefritis, Henoch-Schönleinov nefritis, membranoproliferacijski glomerulonefritis, lupus nefritis, bolest minimalne promjene, postinfekcijski glomerulonefritis i brzo progredirajući glomerulonefritis. Kako neke od ovih bolesti mogu promijeniti liječenje i prognozu bubrežne bolesti kod dijabetičnih bolesnika, patološki nalaz u mokraći ili pogoršanje bubrežne funkcije koji nisu u skladu s naravom dijabetične nefropatije ukazuju na mogućnost nedijabetične bubrežne bolesti i zahtijevaju podrobniju procjenu. Opisuje se bolesnik sa šećernom bolešću tip 1 kod kojega je napravljena biopsija bubrega zbog teške proteinurije i nefrotskog sindroma. Biopsija bubrega je pokazala dijabetičnu nefropatiju, ali i fokalnu segmentnu glomerulosklerozu. Prema našim saznanjima, ovo je prvi objavljeni slučaj primarne žarišne segmentne glomeruloskleroze udružene s dijabetičnom nefropatijom i dijabetičnom retinopatijom, s izvrsnim odgovorom na terapiju.The association of diabetic nephropathy with primary glomerulonephritis in type 1 diabetes is rare. Several reports have shown that primary glomerulonephritis can be superimposed on diabetic nephropathy. These glomerulonephritides include idiopathic membranous glomerulonephritis, IgA glomerulonephritis, Henoch-Schönlein nephritis, membranoproliferative glomerulonephritis, lupus nephritis, minimal change disease, postinfectious glomerulonephritis and rapidly progressive glomerulonephritis. Because some of these disorders can alter the management and prognosis of renal disease in diabetic patients, the appearance of urinary abnormalities or deterioration in renal function inconsistent with the natural history of diabetic nephropathy raises the possibility of a nondiabetic renal disease and should lead to a more detailed evaluation. We report on a patient with type 1 diabetes that underwent renal biopsy because of heavy proteinuria and nephrotic syndrome. Renal biopsy showed diabetic nephropathy coexistent with focal segmental glomerulosclerosis. To the best of our knowledge, this is the first reported case of primary focal segmental glomerulosclerosis associated with diabetic nephropathy and diabetic retinopathy, with excellent therapeutic response

Nefrotski sindrom u starijih osoba

The incidence of certain types of glomerular diseases is different in the elderly as compared with younger patients. Many different histologic appearances can be identified; however, membranous nephropathy is the most common type. Underlying malignancy has been thought to be responsible for 5 to 10 percent of cases of membranous nephropathy in adults, with the highest risk in patients over age 60. A solid tumor such as carcinoma of the lung or colon is most frequently involved. It is presumed that tumor antigens are being deposited in the glomeruli, which is followed by antibody deposition and complement activation, leading to epithelial cell and basement membrane injury and proteinuria due to the associated increase in glomerular permeability. In the present study, 33 patients aged over 60 with nephrotic syndrome were analyzed. Fourteen (42%) patients had membranous nephropathy, three of them with underlying malignancy.Incidencija pojedinih tipova glomerulonefritisa u starijih osoba razlikuje se u usporedbi s mlađim bolesnicima. U starijih osoba mogu se dijagnosticirati različiti oblici glomerulonefritisa, no najčešća je membranska nefropatija. Ovaj oblik glomerulonefritisa je u 5% do 10% bolesnika povezan s malignim tumorom. Najčešći oblici malignih tumora udruženih s membranskom nefropatijom su karcinomi pluća i kolona. Pretpostavlja se da se tumorski antigen odlaže u glomerulima, što izaziva taloženje protutijela i aktiviranje komplementa. To pak izaziva oštećenje epitelnih stanica i bazalne membrane glomerula te proteinuriju. U radu je analizirano 33 bolesnika s nefrotskim sindromom. Svi su bolesnici bili stariji od 60 godina. Membranska nefropatija je dijagnosticirana u 14 (42%) bolesnika, a kod troje bolesnika je ovaj oblik glomerulonefritisa bio udružen s malignom bolešću