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The Thrombotic Microangiopathy Banff Working Group (TMA-BWG) was formed in 2015 to survey current practices and develop minimum diagnostic criteria (MDC) for renal transplant TMA (Tx-TMA). To generate consensus among pathologists and nephrologists, the TMA BWG designed a 3-Phase study. Phase I of the study is presented here. Using the Delphi methodology, 23 panelists with >3 years of diagnostic experience with Tx-TMA pathology listed their MDC suggesting light, immunofluorescence, and electron microscopy lesions, clinical and laboratory information, and differential diagnoses. Nine rounds (R) of consensus resulted in MDC validated during two Rs using online evaluation of whole slide digital images of 37 biopsies (28 TMA, 9 non-TMA). Starting with 338 criteria the process resulted in 24 criteria and 8 differential diagnoses including 18 pathologic, 2 clinical, and 4 laboratory criteria. Results show that 3/4 of the panelists agreed on the diagnosis of 3/4 of cases. The process also allowed definition refinement for 4 light and 4 electron microscopy lesions. For the first time in Banff classification, the Delphi methodology was used to generate consensus. The study shows that Delphi is a democratic and cost-effective method allowing rapid consensus generation among numerous physicians dealing with large number of criteria in transplantation.

The Banff community summoned the TMA Banff Working Group to develop minimum diagnostic criteria (MDC) and recommendations for renal transplant TMA (Tx-TMA) diagnosis, which currently lacks standardized criteria. Using the Delphi method for consensus generation, 23 nephropathologists (panelists) with >3 years of diagnostic experience with Tx-TMA were asked to list light, immunofluorescence, and electron microscopic, clinical and laboratory criteria and differential diagnoses for Tx-TMA. Delphi was modified to include 2 validations rounds with histological evaluation of whole slide images of 37 transplant biopsies (28 TMA and 9 non-TMA). Starting with 338 criteria in R1, MDC were narrowed down to 24 in R8 generating 18 pathological, 2 clinical, 4 laboratory criteria, and 8 differential diagnoses. The panelists reached a good level of agreement (70%) on 76% of the validated cases. For the first time in Banff classification, Delphi was used to reach consensus on MDC for Tx-TMA. Phase I of the study (pathology phase) will be used as a model for Phase II (nephrology phase) for consensus regarding clinical and laboratory criteria. Eventually in Phase III (consensus of the consensus groups) and the final MDC for Tx-TMA will be reported to the transplantation community.

The consequences of graft failure after liver transplantation (LT) range far beyond the liver. The kidneys are often affected, where persistent and progressive cholestasis can result in acute kidney injury (AKI) leading to the development of bile cast nephropathy (BCN). BCN is an often unrecognized condition that is characterized by proximal tubulopathy and the formation of bile casts in the distal tubules, which is almost diagnosed exclusively on a kidney biopsy or autopsy. This condition is potentially reversible, provided the bilirubin levels can be reduced early. LT may represent a treatment option in the case of irreversible liver (or liver graft) failure, which is beneficial for both the liver and the kidney. This paper reports a case of BCN in a patient with idiopathic graft failure after LT. Despite his chronic kidney disease, liver re-transplantation led to the successful improvement of his AKI.

Small-vessel vasculitis (SVV) is the inflammation of the vessel wall that can result in hemorrhage and/or ischemia. Among the histological findings in SVV are increased infiltrating neutrophils, which, due to their oxidative burst and myeloperoxidase activity, release excessive reactive oxygen species, triggering a chain reaction of lipid peroxidation and yielding reactive aldehydes such as acrolein. The implication of oxidative stress in the pathogenesis of SVV was studied, focusing on acrolein immunohistochemistry in the affected skin vessels and systemic stress response. Samples from SVV patients and healthy subjects were collected and analyzed for total serum peroxides, total antioxidant capacity, inflammatory and immunological parameters, as well as for the presence of acrolein–protein adducts in the skin tissue specimens. The obtained data showed that systemic redox homeostasis and iron metabolism are altered in SVV patients. Possible biomarkers in the evaluation of oxidative status, disease activity and prevalence were indicated. Furthermore, a strong correlation between the accumulation of acrolein–protein adducts in the skin and the progression of the disease was revealed. Thus, the results of this study demonstrate that SVV is not only associated with systemic oxidative stress but also with tissue-specific oxidative stress that promotes acrolein formation and protein modification correlating with the severity of cutaneous vasculitis.

Trombotična mikroangiopatija (TMA) je patohistološki entitet obilježen stvaranjem tromba u mikrocirkulaciji, a klinički se definira posljedičnom mikroangiopatskom hemolitičkom anemijom (MAHA) i trombocitopenijom uz oštećenje ciljnih organa, najčešće akutnim oštećenjem bubrega (ABO). Određivanje etiologije može biti složeno. Oblik bolesti trombotična trombocitopenična purpura (TTP) uzrokovan je smanjenom aktivnošću proteaze ADAMTS13. Većina drugih oblika tzv. sekundarne TMA, vezana je etiološki uz neki patogeni proces u organizmu, najčešće hipertenzivnu krizu. Međutim, i u tim stanjima moguć je poremećaj sustava komplementa, što je glavno etiološko obilježje primarnog atipičnog hemolitičko-uremijskog sindroma (aHUS). Zbog toga je važna serološka analiza sustava komplementa, a u nekim slučajevima i njegova genska analiza. Prikazujemo karakteristike deset pacijenata kod kojih su prisutni laboratorijski i/ili patohistološki elementi TMA i u kojih je učinjena i serološka i genska analiza sustava komplementa. U troje pacijenata nađene su patogene ili vjerojatno patogene genske varijante povezane s dijagnozom primarnog aHUS-a. Svi oni su imali MAHA i ABO te patohistološki dokazanu TMA. Kod druge skupine od troje pacijenata nađena je na biopsiji bubrega TMA, ali su svi ostali rezultati (uključujući gensku analizu sastavnica komplementa) bili neupadljivi. Radilo se o pacijentima koji su se prezentirali hipertenzivnom krizom, a testiranje je provedeno u svrhu predtransplantacijske obrade. Kod preostalih četvero pacijenata pronađene su rizične genetske varijante za razvoj aHUS-a. Svi ovi pacijenti (osim jednog) imali su MAHA + ABO. U dva pacijenta nije nađena TMA u tkivu bubrega, no biopsija je učinjena mjesec dana nakon akutne bolesti. Genetska analiza sustava komplementa preporučuje se učiniti ako nema jasnoga sekundarnog uzroka TMA ili ako je važna za određivanje terapije, odnosno za transplantaciju bubrega.

Uvod: IgA-nefropatija (IgAN) ima varijabilnu prezentaciju i prognozu. Međunarodni alat za predviđanje rizika u IgAN-u (IgAN-PT, od engl. International IgA Nephropathy Prediction Tool) predviđa napredovanje bubrežne bolesti do završnog stupnja ili smanjenje procijenjene glomerulske filtracije (eGFR) za 50%. Preporučuje se optimalna suportivna terapija najmanje tri mjeseca, praćena šestomjesečnom primjenom glukokortikoida samo u bolesnika s velikim rizikom napredovanja. Cilj: Istražiti koji su bolesnici imali veću vjerojatnost primiti imunosupresivnu terapiju (IS) te ishode liječenih IS-om. Ispitanici i metode: Retrospektivno kohortno istraživanje 48 bolesnika (33 muškarca), medijana dobi 50 godina (interkvartilni raspon, IQR, od engl. interquartile range 35 – 59), medijana praćenja 43 mjeseca (IQR 18 – 54), liječenih u Kliničkoj bolnici Merkur s novodijagnosticiranim idiopatskim IgAN-om u razdoblju od 2012. do 2021. godine. Rezultati: Imunosupresiju je primilo 17 bolesnika i oni su češće imali mezangijsku (M) (82% prema 54%, p=0,05), endokapilarnu hipercelularnost (E) (65% prema 21%, p=0,004) i polumjesece (C) (41% prema 14%, p=0,04). U odnosu na one bez IS-a nije bilo značajne razlike u eGFR-u kod biopsije (52 (IQR 38 – 81) prema 46 (IQR 30 – 72) ml/min/1,73 m2, p

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.

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.

Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are part of the spectrum of kidney disorders caused by pathogenic variants in α3, α4, or α5 chains of the collagen type IV, the major structural component of the glomerular basement membrane (GBM). Using targeted next-generation sequencing (NGS), 34 AS/TBMN patients (58.8% male) from 12 unrelated families were found positive for heterozygous c.2881+1G>A variant of the COL4A3gene, that is considered disease-causing. All patients were from the continental or island part of Croatia. Clinical, laboratory, and histopathological data collected from the medical records were analyzed and compared to understand the clinical course and prognosis of the affected patients. At the time of biopsy or first clinical evaluation, the mean age was 31 years (median: 35 years; range: 1 – 72 years). Hematuria was present in 33 patients (97.1%) and 19 (55.9%) patients had proteinuria. There were 6 (17.6%) patients with hearing loss, 4 (11.8%) with ocular lesions, and 11 (32.4%) with hypertension. Twenty-three (67.6%) patients had proteinuria at follow-up, and 5 (14.7%) patients with the median age of 48 years (range: 27-55) progressed to kidney failure, started dialysis, or underwent kidney transplantation. Of the 13 patients who underwent kidney biopsy, 4 (30.8%) developed focal segmental glomerulosclerosis (FSGS), and 8 (66.7%) showed lamellation of the GBM, including all patients with FSGS. It is essential to conduct a detailed analysis of each collagen type IV genetic variant to optimize the prognosis and therapeutic approach for affected patients.

We report a rare case of nephritic syndrome underlying dense deposit disease (DDD) with alternative complement pathway dysfunction explained with both C3 nephritic factor (C3NeF) antibodies and DDD associated polymorphism of factor H. An 8-year-old boy presented with macroscopic hematuria, hypertension and periorbital edema followed by persistently low C3 during the 8-week follow-up. Positive C3 staining on immunofluorescence microscopy, supported by dense deposits within the glomerular basement membrane on electron microscopy, confirmed the diagnosis of DDD. Preliminary tests for complement activation showed decreased classic pathway and deficient alternative complement pathway, as well as slightly positive C3NeF, supporting the diagnosis of DDD. Genetic analysis revealed a polymorphism of the complement factor H gene with an increased risk of developing DDD. Supportive therapy led to satisfactory recovery of renal function and normalization of C3. Given the poor prognosis of the disease, proper approach to such specific glomerulopathy is important to avoid or at least slow down progression to end-stage renal disease.

Introduction: primary membranous nephropathy (pMN) is glomerulopathy caused in the majority of cases by autoantibodies to Phospholipase-A2 receptors (PLA2R-AB). This study aimed to evaluate the clinical course and outcomes of the patients with pMN regarding PLA2R-AB status. Patients and methods: 32 patients (21 males, 11 females) with renal biopsy-proven pMN were included in the study. PLA2R-AB (ELI SA method) and outcomes (defined according to KDIGO) were evaluated after 21 and 64 months of follow-up in 28 patients. Results: 19 patients had positive PLA2R-AB (>20 RU /ml) (59.3%), with median titer of 97 (21-1418 RU /ml). The rate of remission in low PLA2R-AB titer group (< 200 RU /ml) after 21 months was significantly higher than in high PLA2R-AB group (> 200 RU /ml) (90% vs. 50%, p=0.045), and after 64 months the difference was not significant (80% vs. 50%, p=0.210). The relapse rate after 64 months was higher in the high PLA2R-AB group (87% vs. 63%). Multivariant linear regression found serum creatinine (ß=0.682, p

Aim. To investigate morphological findings of zero-time biopsies analyzed at the Department of Nephropathology and Electron Microscopy, Dubrava University Hospital, Zagreb. Materials and methods. The retrospective search of data was performed for the period from 2006 to 2018. A total of 316 zero-time renal biopsies were analyzed. Glomerular basement membrane (GBM) thickness was remeasured in 84 zero-time biopsies and 80 protocol biopsies of the same patients 12 months after transplantation. Results and conclusion. The acute tubular injury was present in 90% and glomerular pathology in 17% of zero-time biopsies, with thin basement membranes (TBM ) being the most common entity (13%). Chronic graft changes were evaluated according to Banff classification. Most cases showed Banff scores ci0 (82.6%) and ct0 (65.1%). Banff scores cv2 and cv3 were present in 13% and ah2 and ah3 in 36.4% of specimens. Among 84 remeasured zero-time samples, TBM was present in 26 patients (31%). There were no differences between Banff scores and clinical parameters 12 months after transplantation between recipients with TBM and recipients with normal GBM thickness. Zero-time renal biopsy is of great importance for allograft assessment and comparison with consecutive biopsies. Further investigation is needed to determine the long-term significance of TBM on graft survival.

Background: This report describes data collected by the Croatian Registry of Renal Biopsies (CRRB) for the year 2019. Patients and methods: nine centers (82%) provided data for 255 native kidney biopsies. We assessed the anthropometric data, data on serum creatinine concentration (sCr), 24 h proteinuria, haematuria, serum albumin level, arterial hypertension, histological diagnosis, and complications after renal biopsy. Results: examined group consisted of 58% males, median age 58 y (18-80 y) and 42% women, median age 57 y (20-86 y). Males had a more impaired renal function at the time of renal biopsy, nephrotic syndrome, and hypertension. The most prevalent clinical presentation were urinary abnormalities (34.9%). Among all biopsy cases, primary glomerular diseases were the most often found histology group (41.5%), and IgA nephropathy was the most frequent diagnosis( 47.1%). Among secondary glomerular diseases, pauci-immune glomerulonephritis (PIGN) was most often found (30.9%). The highest proteinuria was observed in minimal change disease and diabetic nephropathy (DN). The highest sCR values were found in membranoproliferative glomerulonephritis (MPGN) and necrotizing vasculitis. Patients with MPGN and DN had the highest blood pressure levels. Conclusion: CRRB provides important data on the epidemiology of biopsy-proven kidney diseases from the whole territory of Croatia

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.

Alport syndrome (AS) is a severe inherited glomerulopathy caused by mutations in the genes encoding the α-chains of type-IV collagen, the most abundant component of the extracellular glomerular basement membrane (GBM). Currently most AS mouse models are knockout models for one of the collagen-IV genes. In contrast, about half of AS patients have missense mutations, with single aminoacid substitutions of glycine being the most common. The only mouse model for AS with a homozygous knockin missense mutation, Col4a3-p.Gly1332Glu, was partly described before by our group. Here, a detailed in-depth description of the same mouse is presented, along with another compound heterozygous mouse that carries the glycine substitution in trans with a knockout allele. Both mice recapitulate essential features of AS, including shorten lifespan by 30–35%, increased proteinuria, increased serum urea and creatinine, pathognomonic alternate GBM thinning and thickening, and podocyte foot process effacement. Notably, glomeruli and tubuli respond differently to mutant collagen-IV protomers, with reduced expression in tubules but apparently normal in glomeruli. However, equally important is the fact that in the glomeruli the mutant α3-chain as well as the normal α4/α5 chains seem to undergo a cleavage at, or near the point of the mutation, possibly by the metalloproteinase MMP-9, producing a 35 kDa C-terminal fragment. These mouse models represent a good tool for better understanding the spectrum of molecular mechanisms governing collagen-IV nephropathies and could be used for pre-clinical studies aimed at better treatments for AS.

The spatiotemporal expression of α-tubulin, inversin and dishevelled-1 (DVL-1) proteins associated with the Wnt-signaling pathway, and primary cilia morphology were analyzed in developing kidneys (14th–38th developmental weeks), healthy postnatal (1.5- and 7-years old) and pathologically changed human kidneys, including multicystic dysplastic kidneys (MCDK), focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome of the Finnish type (CNF). The analysis was performed by double immunofluorescence, electron microscopy, semiquantitative and statistical methods. Cytoplasmic co-expression of α-tubulin, inversin and DVL-1 was observed in the proximal convoluted tubules (pct), distal convoluted tubules (dct) and glomeruli (g) of analyzed tissues. During kidney development, the overall expression of α-tubulin, inversin and DVL-1 decreased, while in the postnatal period slightly increased. The highest expressions of α-tubulin and inversin characterized dct and g, while high DVL-1 characterized pct. α-tubulin, inversin and DVL-1 expression pattern in MCDK, FSGS and CNF kidneys significantly differed from the healthy control. Compared to healthy kidneys, pathologically changed kidneys had dysmorphic primary cilia. Different expression dynamics of α-tubulin, inversin and DVL-1 during kidney development could indicate that switch between the canonical and noncanonical Wnt-signaling is essential for normal kidney morphogenesis. In contrast, their disturbed expression in pathological kidneys might be associated with abnormal primary cilia, leading to chronic kidney diseases.