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Cilj: Iako je transplantacija bubrega najbolja metoda nadomještanja bubrežne funkcije, još uvijek postoji potreba za poboljšanjem dugoročnih ishoda. Cilj rada bio je utvrditi neovisnu povezanost demografskih čimbenika primatelja i darivatelja, osnovne bubrežne bolesti, trajanja liječenja dijalizom, tkivne nepodudarnosti i senzibilizacije s ishodima transplantacije u suvremenoj kohorti pacijenata kojima je presađen bubreg. Ispitanici i metode: U istraživanje su uključeni pacijenti kojima je transplantiran bubreg u Kliničkoj bolnici Merkur od lipnja 2007. do kraja 2018. god. Ishodi transplantacije praćeni su do 31. 12. 2019. godine. Najkraće vrijeme praćenja bila je jedna godina. Podaci su prikupljeni korištenjem izvješća iz aplikacije Eurotransplant Network Information System (ENIS; www.eurotransplant.org). Preživljenje je prikazano Kaplan-Meierovim krivuljama. Povezanost preživljenja s određenim obilježjima primatelja i darivatelja analizirana je univarijatnom i multivarijatnom Coxovom regresijom. Rezultati: U razdoblju od lipnja 2007. do konca 2018. presađeno je 480 bubrega u 472 pacijenta. 10-godišnje preživljenje pacijenata iznosilo je 72 %. Desetgodišnje preživljenje bubrega cenzurirano za smrt pacijenata s bubregom u funkciji bilo je 93 %. U multivarijatnoj analizi jedino dob primatelja pri transplantaciji, šećerna bolest kao uzrok osnovne bubrežne bolesti i trajanje liječenja dijalizom ostali su neovisno povezani s preživljenjem pacijenata. Zaključak: Transplantacija bubrega rezultira odličnim dugoročnim preživljenjem bubrega. Potrebno je poboljšati dugoročno preživljenje pacijenata, prevencijom, ranim otkrivanjem i intenzivnim liječenjem kroničnih bolesti., Aim: Although kidney transplantation is the best method of replacing renal function, there is still a need to improve long-term outcomes. The aim of this study was to determine the independent association of recipient and donor demographic factors, underlying renal disease, duration of dialysis treatment, tissue typing mismatch, and sensitization with transplant outcomes in a contemporary cohort of kidney transplant patients. Patients and methods: The study included patients who had a kidney transplantation at Clinical Hospital Merkur from June 2007 to the end of 2018. Transplant outcomes were monitored until December 31, 2019. The minimum follow-up time was 1 year. Data were collected using reports from the Eurotransplant Network Information System (ENIS) application (www.eurotransplant.org). Survival is shown by Kaplan-Meier curves. The association of survival with specific recipient and donor characteristics was analyzed by univariate and multivariate Cox regression. Results: In the period from June 2007 to the end of 2018, 480 kidneys were transplanted in 472 patients. The 10-year patient survival was 72%. Ten-year renal survival censored for the death of renal function patients was 93%. In the multivariate analysis, only recipient age at transplantation, diabetes as the cause of underlying renal disease and duration of dialysis remained independently associated with patient survival. Conclusion: Long-term graft survival is excellent after kidney transplantation. Long-term patient survival can be improved by prevention, early detection and intensive treatment of chronic diseases.

Over the past 2 decades, scoring systems for multiple glomerular diseases have emerged, as have consortia of pathologists and nephrologists for the study of glomerular diseases, including correlation of pathologic findings with clinical features and outcomes. However, one important limitation faced by members of these consortia and other renal pathologists and nephrologists in both investigative work and routine practice remains a lack of uniformity and precision in clearly defining the morphologic lesions on which the scoring systems are based. In response to this issue, the Renal Pathology Society organized a working group to identify the most frequently identified glomerular lesions observed by light microscopy and electron microscopy, review the literature to capture the published definitions most often used for each, and determine consensus terms and definitions for each lesion in a series of online and in-person meetings. The defined lesions or abnormal findings are not specific for any individual disease or subset of diseases, but rather can be applied across the full spectrum of glomerular diseases and within the context of the different scoring systems used for evaluating and reporting these diseases. In addition to facilitating glomerular disease research, standardized terms and definitions should help harmonize reporting of medical kidney diseases worldwide and lead to more-precise diagnoses and improved patient care.

BACKGROUND AND AIMS Rituximab (RTX) showed some efficacy in treatment of minimal change disease (MCD) and primary focal segmental glomerulosclerosis (pFSGS) [1]. The results of its off-label use and as steroid-sparing agent were especially promising in steroid-dependent, frequently relapsing or steroid-resistant forms of MCD and pFSGS in adults [2]. METHOD All patients treated with RTX in Department of Nephrology and Dialysis, University Hospital Dubrava, Zagreb, were retrospectively reviewed. Complete remission (CR), steroid-resistant nephrotic syndrome (SRNS), steroid-dependent nephrotic syndrome (SDNS), multidrug-resistant SRNS (MDR-SRNS) and calcineurin inhibitor (CNI)-resistant SRNS were defined according to KDIGO 2021 [3]. RESULTS Of 82 patients treated with RTX, 11 patients had biopsy proven MCD and pFSGS. Table 1 summarizes relevant demographic, clinical and treatment data. RTX was applied in five patients with SDNS, four patients with MDR-SRNS, one patient with CNI-resistant SRNS and one patient with active hepatitis C and newly onset MCD as a first line therapy. Median follow-up after initial diagnosis and RTX application was 122.9 (range 30–219) and 20 (range 3–117) months, respectively. All patients were initially treated with steroids, and RTX was the drug most commonly applied after treatment with CNI and cyclophosphamide (CYC). Median proteinuria at the time of RTX application was 10 g/day (range 2.5–16.7), 10 patients had preserved kidney function and only 1 patient with collapsing FSGS (case 11) had severe acute kidney injury. Mean cumulative dose of RTX for induction was 1700 mg and short course of steroids was used concomitantly in 10 cases (except case 5). CR was achieved in seven cases (six cases of MCD and one case of MDR-FSGS). Three of seven patients with CR to RTX experienced relapse of disease. Time to relapse was 6, 15 and 40 months in case 5, 3 and 11, respectively. Repeated RTX application led to CR in all three cases. CR persisted in five patients even after the steroids cessation. There were no serious adverse effects of RTX administration in our cohort. CONCLUSION RTX showed respectable efficacy in our cohort of adults with SDNS-MCD and in case of MDR collapsing FSGS. Although statistical comparison was not performed because of small number of patients, it seems that RTX is more effective in group of SDNS than MDR-SRNS. In our cohort, patients with relapse of RTX-sensitive disease responded to repeated application. Role of RTX in treatment of MCD and pFSGS should be evaluated in randomized clinical trials.

Collapsing glomerulopathy (CG) or collapsing focal segmental glomerulosclerosis (cFSGS) is an aggressive disease with a high tendency of progression to end-stage renal disease due to common resistance to conventional immunosuppressants. Rituximab (RTX), a monoclonal antibody against CD20 B cells, showed some benefit in the treatment of CG. We are reporting about female patients with an idiopathic form of CG presenting with nephrotic syndrome (NS) and renal insufficiency resistant to several immunosuppressive agents such as steroids (ST), calcineurin inhibitors (CNI), and cyclophosphamide (CYC). This multidrug-resistant disease responded to RTX with complete remission. Forty-four months after initial RTX administration, a relapse of CG with severe NS and acute renal insufficiency occurred. Repeated application of RTX led to complete remission again. To the best of our knowledge, we are reporting the first case of the relapsing multidrug-resistant form of CG, which responded to RTX. Current data about the treatment of CG with RTX is lacking and is based on rare case reports and small case series. Thus, our report can contribute to determining the role of RTX in the treatment of CG.

Hrvatsko katoličko liječničko društvo (HKLD) laička je udruga koja djeluje u okrilju Katoličke Crkve. Društvo je osnovano 1991. godine i „okuplja doktore medicine, doktore dentalne medicine, magistre farmacije, magistre medicinske biokemije i druge zdravstvene djelatnike visoke stručne spreme radi promicanja kršćanskih načela u zaštiti zdravlja naroda i čuvanju ljudskog života od začeća do prirodne smrti“. Osnovni cilj ovog rada je prikazati prvih deset godina rada HKLD-a od njegova osnutka 1991. godine, preko raznih izazova i aktivnosti važnih za to razdoblje do proslave prvog desetljeća postojanja 2001. godine.

Background and Aims After membranous nephropathy, focal segmental glomerulosclerosis (FSGS) is the most common cause of nephrotic syndrome in European population. According to Columbia classification, there are five histological variants of FSGS defined on light microscopy (tip, cellular, perihilar, collapsing and not otherwise specified - NOS) and this classification has a prognostic significance. The aim is to compare features and outcomes of tip and cellular variant of primary FSGS. Method All patients with FSGS were identified by a retrospective review of the Registry of kidney biopsies at the Department of Nephrology and Dialysis, Dubrava University Hospital, Zagreb, from 2003 until 2020. Each kidney specimen was analyzed by light, immunofluorescent and electron microscopy and Columbia classification was applied by experienced nephropathologist. Patients with primary FSGS met following criteria: full nephrotic syndrome and diffuse podocyte foot process effacement in absence of secondary causes of FSGS. Laboratory findings were obtained for every patient at the time of biopsy and following outpatient visits. Complete remission was defined as proteinuria < 0.3 g/day with normal kidney function and partial remission as proteinuria 0.3 - 3.5 g/day. Variables are expressed as median ± IQR (interquartile range) and frequencies. Statistical comparison between groups of patients with tip and cellular variant of primary FSGS and disease outcome analysis were done. Results Out of 200 patients with FSGS, 59 (29.5 %) had primary form of disease. Tip variant was the most common form of primary FSGS (22 patients, 37 %) followed by NOS (20, 34 %), cellular (13, 22 %), perihilar (2, 3.5 %) and collapsing (2, 3.5 %) variant. Demographic and clinical features with initial laboratory findings are shown in Table 1. There were no significant differences between two groups in all analyzed variables in Figure 1. All patients were treated by anti-RAAS agents and steroids. Median follow-up was 55 months (range 1 – 196 months), and followup data were unavailable for three patients. Figure 2 shows treatment regimens in both patient grouos with treatment outcomes. Remission rate was significantly higher in tip variant (90 % vs. 41 %, p = 0.002). There was no difference in relapse rate between the two groups (p = 0.717). Conclusion There were no significant differences in clinical features and laboratory findings at the time of clinical presentation between tip and cellular variant of primary FSGS. Patients with tip variant had significantly higher remission rate than patients with cellular variant.

Background and Aims ANCA associated vasculitis (AAV) are usually classified according to clinical presentation (Chapel-Hill consensus conference). There is however suggestion by some authors that AAVs could be classified according to ANCA specificity. We aimed to compare AAV patients in our cohort according to serological phenotype. Method This study included 106 consecutive AAV patients with renal involvement in the period from 2007-2017. We performed renal biopsy on patients using automatic 16 Gauge needle. Light, immunofluorescent and electronic microscopy were performed. Category variables were analysed with Fisher Exact testom and continuous with Kruskal-Wallis testom. Statistical difference was then analysed posthoc with Chi-square test. Primary outcomes were combined outcome progression to end-stage renal disease, defined as persistent (more than three months) need for renal replacement therapy or permanent reduction of EGFR to Results The study included 106 AAV patients with renal involvement: 66 (61,1%) MPA, 20 (18,5%) GPA, 20 (18,5%) RLV. There were 14 (13%) PR3-ANCA positive patients, 57 (52,8%) MPO ANCA positive, 5 (4,6%) PR3-ANCA+MPO-ANCA and 32 (29,6%) ANCA negative patients. Average SCr was 316,5 μmol/l (IQR 207,0-548,5), 24-hour proteinuria median was 1,7g/24h (IQR 0,8-2,8). Clinicaly PR3 positive AAVs had significantly more ENT (p Conclusion Serological classification of AAVs is an interesting way for overcoming the limitations of clinical classification. Apart from differences between MPO, PR3 and double positive AAVs, it appears there are even more significant differences between ANCA positive and negative ones.

Background and Aims In recent years there were many studies explaining the role of alternative complement pathway (aCP) in etiopathogenesis of the ANCA associated vasculitis (AAV) and weather it affects patient outcomes. We hypothesized the importance of the C3 positive staining in glomeruli and that there could be differences between clinical, serological and histological phenotypes in AAV patients. Method This study included 106 consecutive AAV patients with renal involvement in the period from 2007-2017. We performed renal biopsy on patients using automatic 16 Gauge needle. Light, immunofluorescent and electronic microscopy were performed. Category variables were analysed with Fisher Exact testom and continuous with Kruskal-Wallis testom. Statistical difference was then analysed posthoc with Chi-square test. Primary outcomes were combined outcome progression to end-stage renal disease, defined as persistent (more than three months) need for renal replacement therapy or permanent reduction of EGFR to Results The study included 106 AAV patients with renal involvement: 66 (61,1%) MPA, 20 (18,5%) GPA, 20 (18,5%) RLV. There were 14 (13%) PR3-ANCA positive patients, 57 (52,8%) MPO ANCA positive, 5 (4,6%) PR3-ANCA+MPO-ANCA and 32 (29,6%) ANCA negative patients. Average SCr was 316,5 μmol/l (IQR 207,0-548,5), 24-hour proteinuria median was 1,7g/24h (IQR 0,8-2,8). Histologicaly (Berden classification) 43 (39,8%) patients had crescentic, 19 (17,6%) focal, 34 (31,5%) mixed and 12 (11,1%) sclerotic class. Out of all, 48,5% MPA patients had C3 deposits in glomeruli compared to 25% GPA and 35% RLV though statistical significance was not reached (p=0,1). Same applied for serological phenotypes: MPO-ANCA and ANCA negatives had more C3 deposits but statistical significance was not reached (p=0,6). When comparing histopathological classes there was strong tendency of crescentic class having more C3 deposits (p=0,076) compared to focal and mixed. In sclerotic class 50% had C3 deposits but C3 deposits can be ordinary found in sclerotic lesions so the interpretation is more challenging. Interestingly patients requiring haemodialysis had strong tendency of having more C3 deposits compared to those not needing haemodialysis treatment (p=0,09). Conclusion Glomerular C3 deposits in kidney tissue samples could prove to be a useful tool for perhaps predicting the severity and the course of the disease. Though differences between various groups in our cohort didn't have statistical significance, there was a tendency for MPA patients, those with MPO-ANCA and those with crescentic class of having higher proportion of C3 deposits in glomeruli compared to other groups. This could suggest more aCP activation in MPO positive AAV. Also there was strong tendency of patients requiring dialysis having higher proportion of C3 deposits compared to non-dialysis patients which could signify C3 deposition of being the hallmark of more severe renal involvement in AAV patients. This data needs further confirmation from future studies.

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.

The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified ‘mutational hotspots’ (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that ‘well-established’ functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common ‘incidental’ findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3–COL4A5 genes remains a challenge.

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.

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., Highlights • Two mouse models were generated that recapitulate essential features of AS patients. • Glomeruli and tubuli respond differently to mutant collagen IV protomers. • The mutant colIV protomers in glomeruli probably undergo a cleavage process by MMP9. • The two AS mouse models represent a good tool for studying collagen-IV nephropathies. • These models could be used for pre-clinical studies aimed at better treatments.

Glomerular kidney diseases are one of the major causes of renal failure in patients preparing for kidney transplantation. Clinical monitoring of these patients may be a great challenge because of the variable course of various types of glomerular diseases, as well as the possibility of disease recurrence in the transplanted kidney. Focal segmental glomerulosclerosis, IgA nephropathy, C3 glomerulopathy, and membrane nephropathy before and after transplantation are described in this text. Risk factors and early detection of disease recurrence, clinical features, histologic characteristics, therapeutic options, modification of immunosuppressive therapy, and treatment outcomes for various forms of glomerulonephritis in the transplanted kidney are the topics of this review article.

Background and Aims Dialysis dependence and ESRD are known complications of ANCA associated vasculitis (AAV) with renal involvement. What is not so often discussed is the role of dialysis treatment at the time of diagnosis and how it affects patient outcomes as well as characteristics of such patients. We present data showing the importance of dialysis treatment at the time of diagnosis as the predictor of clinical outcomes. Method This study included 106 consecutive AAV patients with renal involvement in the period from 2007-2017. We performed renal biopsy on patients using automatic 16 Gauge needle. Light, immunofluorescent and electronic microscopy were performed. Primary outcomes were combined outcome progression to end-stage renal disease, defined as persistent (more than three months) need for renal replacement therapy or permanent reduction of EGFR to Results Out of 106 patients (55,6% female, median age 61; IQR 51-70) there were 66 (61,1%) microscopic poliangitiis (MPA), 20 (18,5%) granulomatosis with angitiis and 20 (18,5%) with renal limited vasculitis (RLV). Out of those 14 (13%) were PR3-ANCA positive patients, 57 (52,8%) MPO ANCA positive, 5 (4,6%) PR3-ANCA+MPO-ANCA positive and 32 (29,6%) ANCA negative patients. Average serum creatinine (SCr) levels was 316,5 μmol/l (IQR 207,0-548,5), 24-hour proteinuria median was 1,7g/24h (IQR 0,8-2,8). According to the Berden classification 43 (39,8%) patients had crescentic, 19 (17,6%) focal, 34 (31,5%) mixed and 12 (11,1%) sclerotic class. Follow up time ranged from 1 to 127 months. Median follow up time was 21 months (IQR = 7-44). Median time to diagnosis was 3 months (IQR 2,0-6,0). Patients requiring dialysis treatment at the time of diagnosis were more often MPO – (p=0,04), had more severe anemia (p=0,001), higher CRP (p=0,003), and more pronounced hypoalbuminemia (serums albumin Conclusion The need for dialysis at the time of AAV diagnosis is a strong predictor for ESRD and relapse rate. It is also interesting to further study differences between patients needing dialysis at the time of diagnosis and those who don’t need it.

Background and Aims Kidneys are often damaged in paraproteinemic conditions. Paraproteins are monoclonal immunoglobulins or immunoglobulin fractions that are produced by a clonal population of B- or plasma cell lineage and can cause a variety of histological patterns of kidney injury, such as light chain (AL) amyloidosis or light chain cast nephropathy (LCCN). Monoclonal gammopathy of renal significance (MGRS) represents a group of disorders in which a monoclonal immunoglobulin secreted by B- or plasma cell clone causes renal damage. By definition, these disorders do not meet diagnostic criteria for overt, symptomatic multiple myeloma or a lymphoproliferative disorder, but in contrast to monoclonal gammopathy of undetermined significance (MGUS) there is evidence of end-organ damage that can warrant therapy. Method All patients with paraproteinemic kidney disease were identified by retrospective review of the Hospital Register of kidney biopsies done at Department of Nephrology and Dialysis, in Dubrava University Hospital, Zagreb, from 2009 until 2018. Every kidney biopsy was analyzed by light, immunofluorescent and electron microscopy. Laboratory findings, including serum protein electrophoresis, serum free light chain level and immunofixation of serum proteins, were done for every patient. Clinical and histologic features of patients and features of underlying hematological conditions were analyzed. Results We identified 47 patients (3,28% of all biopsies that were done in that period) with kidney disease with clear hematological background. The mean patients' age at the time of the biopsy was 63 years and 27 of them were females. Two patients had signs of direct infiltration of kidneys with malignant lymphomic cells (non-Hodgkin lymphoma) and were excluded from the analysis. Clinical presentation of the patients at the time of biopsy were: proteinuria in 85% of patients, full nephrotic syndrome in 55%, azotemia in 66% of patients (80% had acute kidney injury of unclear etiology) and hematuria in 12,7%. Most common histologic patterns of kidney injury were AL amyloidosis (45%) and LCCN (30%) but additionally 7 different histological patterns were found: light chain depostion disease, light chain proxymal tubulopathy, fibrillary and imunotactoid glomerulopathy, proliferative glomerulonephritis with monoclonal immunoglobulin deposition, crioglobulinemic glomerulopathy type I and tubulointerstitial damage caused by immunoglobulin deposition. Figure 1 shows main features of patients with AL amyloidosis and cast LCCN. Conclusion Kidney disease can be initial presentation of an underlying paraproteinemia and, as our data showed, can clinicaly present with acute kidney injury, nephrotic or subnephrotic range proteinuria or full nephrotic syndrome. Variety of histologic patterns of kidney injury were described and AL amyloidosis and LCCN were the most common histological findings. Detailed hematologic workup should follow kidney biopsy in order to determine the exact nature and extension of the disease and therefore the most appropriate therapy.

Background and Aims The aim of the research was to evaluate patient and renal as well as relapse free survival in ANCA associated vasculitis (AAV) patients in our center. Despite the advances in understanding pathogenesis of AAVs and advances in treatment, the outcomes of AAV patient differ in various centers. Method This study included 106 consecutive AAV patients with renal involvement in the period from 2007-2017. We performed renal biopsy on patients using automatic 16 Gauge needle. Light, immunofluorescent and electronic microscopy were performed. All the patients were treated with cyclophosphamide and steroids in induction treatment with adjuvant PLEX and dialysis depending on renal function and lung manifestations. Primary outcomes were combined outcome progression to end-stage renal disease, defined as persistent (more than three months) need for renal replacement therapy or permanent reduction of EGFR to Out of 106 patients (55,6% female, median age 61; IQR 51-70) there were 66 (61,1%) microscopic poliangitiis (MPA), 20 (18,5%) granulomatosis with angitiis and 20 (18,5%) with renal limited vasculitis (RLV),There were 14 (13%) PR3-ANCA positive patients, 57 (52,8%) MPO ANCA positive, 5 (4,6%) PR3-ANCA+MPO-ANCA positive and 32 (29,6%) ANCA negative patients. Histologically (Berden classification) 43 (39,8%) patients had crescentic, 19 (17,6%) focal, 34 (31,5%) mixed and 12 (11,1%) sclerotic class. Follow up time ranged from 1 to 127 months. Median follow up time was 21 months (IQR = 7-44). Median time to diagnosis was 3 months (IQR 2,0-6,0). Results During follow up 21 (19,8%) patients died, 26 (24,5%) patients reached ESRD and 10 (9,4%) patients relapsed. There was no significant difference in outcomes between clinical, serological or histological phenotypes. In multivariant analysis independent predictors for death were age (HR = 1,059, 95% CI =1,001-1,120; p = 0,046), anemia (HR = 0,952, 95% CI =0,908-0,998; p = 0,040) and BVAS (HR = 1,093, 95% CI =1,030-1,159; p = 0,003), for ESRD. the need for acute dialysis (HR = 4,674, 95% CI =1,996-10,946; p = < 0,001), and interstitial fibrosis and tubular atrophy (IFTA) percentage over 50% (HR = 2,652, 95% CI =1,157-6,081; p = 0,021). and for relapse rate younger age (HR = 0,924, 95% CI = 0,870-0,981; p =0,010), lower serum creatinine levels (HR = 0,996, 95% CI = 0,992-1,000; p = 0,033), and the need for acute dialysis (HR = 59,545, 95% CI =3,467-1022,665; p = 0,005). Event free survival after 12, 24, 36 and 60 months was for death 83,9, 81,2, 79 and 74,7%, for ESRD 80,6, 77,9, 76,1 and 71% and for relapse 95,3, 88,4, 88,4 and 85%. Conclusion Timely diagnosis and treatment can ensure better outcomes in AAV patients. Though there is an overlap in predictive factors between different cohorts, there are still distinctive differences especially between cohorts from clinical trials and those from observational studies. Our study is among few to show significance of anemia as clinical predictor and IFTA percentage as pathohistological predictor.

Background and Aims IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. The classic manifestation of IgAN is episodic hematuria and proteinuria. Nephrotic syndrome (NS) is not common in IgAN. It is reported to occur in 5-10% of patients with IgAN. Clinical presentation with massive proteinuria is exceptional. Method We retrospectively analyzed patients with pathohistologically proven IgAN who initially presented with 24h proteinuria greater than 10 gr. Here we presented their clinical, biochemical and pathohistological (electron microscopy-EM, was provided in all cases) characteristics with clinical outcomes. Data were taken from Renal biopsy Registry of Department of Nephrology Dubrava University hospital. Results All together 12 patients (10 M, 2 F) average age 53 (range 25-81) years were included. This represents 3,2% of all IgAN patients in our Renal biopsy Registry (presently there are more than 2100 patients in total, 366 with IgAN). Arterial hypertension had 10 out of 12 patients and three patients had diabetes mellitus type 2. Other significant comorbidities included lung adenocarcinoma in one patient, history of preeclampsia, mitral valve replacement surgery and liver cirrhosis, each in one patient. Average serum creatinine level at presentation was 223,9 (90-549) µmol/L and average 24h proteinuria was 14,6 (10,2-32) gr. All patients had haematuria. Renal insufficiency was found in 7 patients and additionally in two patients rapidoprogressive clinical pattern was recognized. Oxford classification was applied for all patients. In all except one, mesangial hypercellularity (M1) was found, endocapillary proliferation (E1) in 4 and cellular crescents in 5 patients (C1 in 4, C2 in 1 patient). The average percentage of globally sclerosing glomeruli was 32% (10-85%) and IFTA was 33% (10-60%), respectively. On EM diffuse podocyte foot processes effacement was documented only in two patients. In patients with diabetes mellitus there were not signs of diabetic nephropathy (i.e. thickened GBM on EM). Two patients who presented with purpuric rash and arthritis were considered to have IgA vasculitis (Henoch Schoenlein purpura). Considering treatment, glucocorticosteroids and RAAS blockators (apart from those who were dialysis dependent) were introduced. Five patients were also treated with cyclophosphamide. Average time of follow-up was 53 months (2-156). Regarding clinical outcomes, 4 patients achieved remission (2 partial and 2 complete). One of those experienced clinical relaps and underwent kidney rebiosy. In one patient stationary course and in another one progression of renal insufficiency were noted. Both patients diagnosed as IgA vasculitis were dialysis depended at presentation and during follow-up period unfortunately died. Two more patients died latter on as a consequence of a non-renal disorders. One more patient who developed ESRD was transplanted but afterwards he rejected the graft. One patient was lost from follow-up. Conclusion Proteinuria is well known independent progression risk factor in IgAN. In presented study we showed that almost one third of IgAN patients who manifested with massive proteinuria ended up in ESRD in relatively short follow-up period.

Alport syndrome (AS) is a genetically heterogenic, structural disorder of the glomerular basement membrane (GBM) due to the mutation of COL4A3, COL4A4, or COL4A5 genes, which clinically presents as progressive hematuric nephritis with ultrastructural changes of the GBM, high tone sensorineural hearing loss, and ocular lesions. About 15% of AS cases have autosomal mutations of COL4A3 and COL4A4 genes, including homozygous and compound heterozygous mutations. Here, we present a case of a two-year-old boy with autosomal recessive Alport syndrome (ARAS) caused by a novel c.193-2A>C COL4A4 mutation. The patient had a delayed motor and sensory development coupled with speech and language delay, megalencephaly, hematuria and proteinuria, and normal tonal audiogram and ophthalmology exam. Extensive genetic, metabolic, and neurologic workup performed at the age of 10 months was unremarkable and patient's megalencephaly was described as familial benign megalencephaly. Kidney biopsy analysis showed characteristic signs of AS. Mutations screening with use of Illumina MiSeq platform revealed that the patient was homozygous for a newly discovered splice acceptor pathogenic variant c.193-2A>C found in COL4A4 at the genomic position chr2:227985866 and both parents were heterozygous carriers. The genetic heterogeneity of AS makes the diagnostic process challenging. Although renal biopsy provides information about the characteristic GBM changes and the degree of renal parenchyma damage (interstitial fibrosis and tubular atrophy ratio), genetic testing is a more sensitive and specific method that also gives insight into potential disease severity and clinical course, and provides the basis for genetic counseling.

AIM: To determinate the prognostic significance of low serum C3 at the time of diagnosis of ANCA- associated vasculitis (AAV). METHODS: Our cohort included 75 consecutive patients with AAV diagnosed from January 2005 to December 2015. C3 levels were measured at the time of diagnosis. Patients were divided into two groups, those with low serum C3 levels (< 0.9 g/l) and those with normal serum C3 levels (0.9-1.8 g/l). We analysed association between serum C3 levels and both combined and singularly patient and renal survival (ESRD). Small number of relapsed patients did not allow for the statistical analysis to be performed as to weather the low serum C3 is associated with relapse rate in AAV patients. RESULTS: Low serum C3 levels were significantly associated with worse combined end-point patient and renal survival (HR 3.079 ; 95% CI 1.231-7.701 ; p = 0.016), and on multivariate adjusted analysis association remained significant (HR 2.831 ; 95% CI 1.093-7.338 ; p = 0.032). For both end- points individually low serum C3 levels were significantly associated with poorer patient survival (HR 6.378 ; 95% CI 2.252-18.065 ; p < 0.001 ; on multivariate adjusted analysis HR 4.315 95% CI 1.350-13.799 ; p = 0.014) and renal survival (HR 3.207 ; 95% CI 1.040-9.830 ; p = 0.043 ; on multivariate adjusted analysis HR 3.679 ; 95% CI 1.144- 11.827 ; p = 0.029). In our study there was no significant association between serological and patohistological phenotypes and serum C3 levels. CONCLUSION: Lower serum C3 levels at the diagnosis is associated with poorer patient and renal outcomes in AAV patients.

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.

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.

Introduction: IgA vasculitis, formerly named Henoch-Schönlein purpura, is a systemic small-vessel vasculitis that occurs commonly in children, while in adults, the disease remains rare. It is characterised by non-thrombocytopenic palpable purpura, arthritis, arthralgia, kidney disease and gastrointestinal pain. This study aimed to determine clinical signs and symptoms, laboratory and pathohistological parameters and therapy of IgA vasculitis in adults with renal involvement, by conducting our research on a sample of patients of a tertiary referral hospital. Research subjects and methods: In this retrospective cohort study, patients treated at Clinical Hospital Dubrava from 2011 to 2019 were included, who were diagnosed with IgA vasculitis, based on clinical, laboratory and pathohistological criteria. Clinical and laboratory parameters, were determined through the use of methods commonly used in clinical practice. In patients with symptoms and signs of kidney involvement and after patients’ consent, kidney biopsy was performed, and analysed by light, immunofluorescence and electron microscopy. Results: twenty-two adults (12 M, 10 F), whose median age was 57, were included in our study. Palpable purpura and nephritis were present in all patients. Thirteen (59.1%) patients had arthralgia and five of them (22.5%) experienced abdominal pain. Respiratory infection preceded vasculitis in six (27.3%) patients, six patients ((27.3%) were taking medications and got vaccinated prior to the occurrence of vasculitis, and in ten (45.4%) patients the predisposing factor was unknown. Asymptomatic hematuria was present in ten (47.6%), subnephrotic proteinuria in three (14.3%), nephrotic syndrome in nine (42.9%) and nephritic syndrome in three (14.3%) patients. According to the findings of kidney biopsy, which was performed on 18 patients, eleven (61.6%) had mesangial proliferation, fourteen (77.8%) had endocapillary proliferation, and eleven (61.6%) had extracapillary (crescents) proliferation. After the diagnosis, renin-angiotensin inhibitors were used by eighteen (81.8%) patients, glucocorticoids by twenty-one (95.5%) and cyclophosphamide by five (22.7%) patients. Patient follow-up was performed for 23 to 84 months and, in the said period, all of them had improved or stagnant renal function, except for one patient who died. Conclusion: Renal manifestations of IgA vasculitis may change the commonly mild course of this disease and lead to an increase in morbidity as well as affect the type and duration of treatment. So, in everyday work, it is important to determine characteristics of renal changes in IgA vasculitis in order for an adequate therapeutic option to be applie., Uvod: IgA-vaskulitis, prije nazivan Henoch-Schönleinova purpura, vaskulitis je malih krvnih žila posredovan imunoglobulinom A (IgA). Najčešće obolijevaju djeca, dok je u odraslih incidencija manja. Kliničkom slikom dominiraju palpabilna, netrombocitopenična purpura, artralgije, artritis, znakovi bubrežne bolesti i abdominalna bol. Cilj ovog istraživanja bio je utvrđivanje kliničkih i laboratorijskih karakteristika te načina liječenja odraslih oboljelih od IgA-vaskulitisa sa zahvaćanjem bubrega na uzorku bolesnika iz jednoga tercijarnog centra. Ispitanici i metode: U retrospektivno kohortno istraživanje uključeni su bolesnici liječeni u razdoblju od 2011. do 2019. godine u Kliničkoj bolnici Dubrava u Zagrebu, kojima je na osnovi kliničkih, laboratorijskih i patohistoloških kriterija dijagnosticiran IgA-vaskulitis. Klinički i laboratorijski parametri određivani su metodama uobičajenima u kliničkoj praksi. U bolesnika sa znakovima zahvaćanja bubrega učinjene su biopsija bubrega i analiza svjetlosnom, imunofluorescentnom i elektronskom mikroskopijom. Rezultati: U istraživanju su sudjelovala ukupno 22 bolesnika (12 muškaraca, 10 žena), medijana dobi 57 godina. Svi su bolesnici imali purpuru i znakove bubrežne bolesti. Artralgije je imalo 13-ero (59,1%) bolesnika, a bol u trbuhu njih 5-ero (22,5%). Infekcija dišnog sustava prethodila je vaskulitisu u 6-ero (27,3%) bolesnika, lijekovi i cjepiva također u njih 6-ero (27,3%), a u 10-ero (45,4%) bolesnika predisponirajući čimbenik bio je nepoznat. Asimptomatsku hematuriju imalo je 10-ero (47,6%) bolesnika, subnefrotsku proteinuriju njih troje (14,3%), nefrotski sindrom 9-ero (42,9%), a nefritički sindrom imalo je također troje (14,3%) bolesnika. Prema nalazu biopsije bubrega, koja je učinjena u 18-ero bolesnika, mezangijsku proliferaciju imalo je njih 11-ero (61,1%), endokapilarnu proliferaciju 14-ero (77,8%), a ekstrakapilarnu proliferaciju (polumjesece) imalo je 11-ero (61,1%) bolesnika. Nakon postavljanja dijagnoze terapiju inhibitorima sustava renin-angiotenzin primalo je 18-ero (81,8%) bolesnika, 21 bolesnik (95,5%) dobivao je glukokortikoide, a njih 5-ero (22,7%) liječeno je ciklofosfamidom. Bolesnici su praćeni tijekom razdoblja od 23 do 84 mjeseca, a u svih se, osim u jedne bolesnice, bubrežna funkcija poboljšala ili je stagnirala. Zaključak: Bubrežne manifestacije IgA-vaskulitisa mijenjaju inače blagi tijek bolesti, dovode do porasta morbiditeta i utječu na trajanje liječenja. Pri svakodnevnom radu valja utvrditi značajke bubrežnih promjena kod IgA-vaskulitisa da bismo na temelju tih obilježja primijenili prikladnu terapiju.

While glomerulosclerosis commonly progresses to kidney failure, its mechanisms are unclear. Using murine models and human samples, the authors show that progressive glomerulosclerosis results from loss of decay-accelerating factor (DAF/CD55) on podocytes, which in turn initiates complement C3aR signaling and downstream IL-1β/IL-1R1–mediated podocyte injury and loss., Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay-accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL-1β/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1β/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement-dependent, IL-1β–induced podocyte injury, potentially identifying new therapeutic targets., Graphical Abstract

In a clinically-relevant model of 4 week, low-dose cisplatin-induced AKI, mice were injected subcutaneously with non small cell lung cancer (NSCLC) cells that harbor an activating Kirsten rat sarcoma viral oncogene homolog (KRAS)G12V mutation. Phospho extracellular signal-regulated kinase1/2 (pERK1/2) expression in kidney and tumors was decreased by the MEK1/2 inhibitors, U0126 and trametinib, that potently inhibit pERK1/2. U0126 resulted in a significant improvement in kidney function, acute tubular necrosis (ATN) and tubular cell apoptosis in mice with AKI. Genes that were significantly decreased by U0126 were heat shock protein 1, cyclin-dependent kinase 4 (CDK4) and stratifin (14–3-3σ). U0126 resulted in a significant decrease in tumor weight and volume and significantly increased the chemotherapeutic effect of cisplatin. Trametinib, a MEK1/2 inhibitor that is FDA-approved for the treatment of cancer, did not result in functional protection against AKI or worse AKI, but dramatically decreased tumor growth more than cisplatin. Smaller tumors in cisplatin or MEK1/2 inhibitor-treated mice were not related to changes in microtubule-associated proteins 1A/1B light chain 3B (LC3-II), p62, cleaved caspase-3, granzyme B, or programmed death-ligand 1 (PD-L1). In summary, despite ERK inhibition by both U0126 and trametinib, only U0126 protected against AKI suggesting that the protection against AKI by U0126 was due to an off-target effect independent of ERK inhibition. The effect of U0126 to decrease AKI may be mediated by inhibition of heat shock protein 1, CDK4 or stratifin (14–3-3σ). Trametinib was more effective than cisplatin in decreasing tumor growth, but unlike cisplatin, trametinib did not cause AKI.

Anti-glomerular basement membrane disease (anti-GBM) is a rare disease usually mediated by IgG autoantibodies. It usually presents as rapidly progressive glomerulonephritis, often accompanied by pulmonary hemorrhage.1 The hallmark of anti-GBM disease are the blood circulating and tissue-bound autoantibodies that target antigenic sites within the glomerular basement membrane (GBM) and sometimes alveolar basement membranes. We present a rare case of anti-GBM disease mediated by IgA autoantibody. A 65-year-old-man presented with gross haematuria and nephrotic range proteinuria and was admitted to the hospital.