The Apical Endocytic-Lysosomal Apparatus in CLCN5 Mutations with Phenotypic-Genotypic Correlations in Three Cases.

Dent disease type 1 is characterized by pathogenic CLCN5 gene variants and impaired receptor-mediated endocytosis in proximal tubules. However, mutation-related abnormalities in proximal tubules have not yet been described. Here, we present three patients with CLCN5 alterations and distinct morphological changes of the apical endocytic-lysosomal apparatus. The proximal tubular ultrastructure was investigated in kidney biopsy samples of three boys genotyped for non-nephrotic proteinuria. Controls: seven patients with nephrotic-range glomerular proteinuria. The genotyping findings revealed an already-known missense mutation in one patient and hitherto undescribed frameshift variants in two patients. Low-molecular-weight proteinuria, focal global glomerulosclerosis, proximal tubular changes, and tubular calcium deposits characterized each case. Three subsets of proximal tubular cells were observed: those without any abnormality, those with aplasia of apical endocytic-lysosomal apparatus and shrinkage of cells, and those with hypoplasia of apical endocytic apparatus, accumulation of proteinaceous substance in dysmorphic lysosomes, and dysmorphic mitochondria. The distribution of subsets varied from patient to patient. In one patient with a frameshift variant, an oxidative stress-like injury of proximal tubular cells and podocytes accompanied the above-mentioned alterations. Focal aplasia/hypoplasia of apical endocytic apparatus and subsequent changes in cytoplasmic organelles characterized proximal tubules in the CLCN5 pathogenic variants.

Phenotypic and Genotypic Features of the FAN1 Mutation-Related Disease in a Large Hungarian Family.

Pathogenic variants in the FAN1 gene lead to a systemic disease with karyomegalic interstitial nephritis (KIN) at the forefront clinically. The phenotypic-genotypic features of a FAN1 mutation-related disease involving five members of a Hungarian Caucasian family are presented. Each had adult-onset chronic kidney disease of unknown cause treated with renal replacement therapy and elevated liver enzymes. Short stature, emaciation, latte-colored skin, freckles, and a hawk-like nose in four patients, a limited intellect in two patients, and chronic restrictive lung disease in one patient completed the phenotype. Severe infections occurred in four patients. All five patients had ceased. Four patients underwent autopsy. KIN and extrarenal karyomegaly were observed histologically; the livers showed no specific abnormality. The genotyping using formalin-fixed tissue samples detected a hitherto undescribed homozygous FAN1 mutation (c.1673_1674insT/p.Met558lfs*4; exon 5) in three of these patients and a heterozygous FAN1 mutation in one patient. The reason for the heterozygosity is discussed. In addition, 56 family members consented to the screening for FAN1 mutation from which 17 individuals proved to be heterozygous carriers; a blood chemistry evaluation of their kidney and liver function did not find any abnormality. The clinical presentation of FAN1-related disease was multifaceted, and not yet described manifestations were observed besides kidney and liver disease. Mutation in this gene should be suspected in adults with small kidneys of unknown cause, elevated liver enzymes, and recurrent infections, even without a family history.

Renal Cell Carcinoma in End-Stage Renal Disease: A Retrospective Study in Patients from Hungary.

INTRODUCTION: End-stage renal disease (ESRD) and acquired cystic kidney disease (ACKD) are known risk factors for renal cell carcinoma (RCC). Hereby, the clinicopathological features of RCCs developed in ESRD were investigated. METHODS: A database consisting of 34 tumors from 31 patients with ESRD among 2,566 nephrectomy samples of RCC was built. The demographic, clinical, and follow-up data along with pathological parameters were analyzed. The RCCs were diagnosed according to the current WHO Classification of Urinary and Male Genital Tumors. RESULTS: Twenty-two tumors developed in men and 12 in women, with a median age of 56 years (range: 27-75 years). The causes of ESRD were glomerulonephritis (n = 7), hypertensive kidney disease (n = 6), autosomal dominant polycystic kidney disease (n = 6), chronic pyelonephritis (n = 4), diabetic nephropathy (n = 3), chemotherapy-induced nephropathy (n = 1), and undetermined (n = 4). ACKD complicated ESRD in 12 patients. The following histological subtypes were identified: clear cell RCC (n = 19), papillary RCC (n = 5), clear cell papillary tumor (n = 5), ACKD RCC (n = 3), and eosinophilic solid and cystic RCC (n = 2). The median tumor size was 31 mm (range: 10-80 mm), and 32 tumors were confined to the kidney (pT1-pT2). There was no tumor-specific death during the period of this study. Progression was registered in 1 patient. CONCLUSION: In our cohort, the most common RCC subtype was clear cell RCC (55%), with a frequency that exceeded international data appreciably (14-25%). The incidence of clear cell papillary tumor and ACKD RCC (14.7% and 8.5%) was lower than data reported in the literature (30% and 40%). Our results indicate a favorable prognosis of RCC in ESRD.

The value of PLA2R antigen and IgG subclass staining relative to anti-PLA2R seropositivity in the differential diagnosis of membranous nephropathy.

BACKGROUND: The diagnostic performance of PLA2R and IgG subclass staining of kidney biopsies relative to anti-PLA2R seropositivity in the differentiation of primary and secondary membranous nephropathy (pMN, sMN) was examined. Besides PLA2R staining - which has a lower specificity than anti-PLA2R antibody serology - there is insufficient knowledge to decide which IgG1-4 subtype immunohistological patterns (IgG4-dominance, IgG4-dominance/IgG1-IgG4-codominance or IgG4-dominance/IgG4-codominance with any IgG subtype) could be used to distinguish between pMN and sMN. METHODS: 87 consecutive Hungarian patients (84 Caucasians, 3 Romas) with the biopsy diagnosis of MN were classified clinically as pMN (n = 63) or sMN (n = 24). The PLA2R and IgG subclass staining was part of the diagnostic protocol. Anti-PLA2R antibodies were determined by an indirect immunofluorescence test in 74 patients with disease activity. RESULTS: For pMN, the sensitivity of anti-PLA2R seropositivity was 61.1%, and the specificity was 90.0%; and similar values for PLA2R staining were 81.0%, and 66.7%, respectively. In all stages of pMN, IgG4-dominance was the dominant subclass pattern, while the second most frequent was IgG3/IgG4-codominance. The sensitivity and specificity scores were: IgG4-dominance 52.2% and 91.7%, IgG4-dominance/IgG3-IgG4-codominance 76.2% and 87.5%, IgG4-dominance/IgG1-IgG4-codominance 64.2% and 75%, and IgG4-dominance/codominance with any IgG subclass 92.1% and 70.8%, respectively. Anti-PLA2R seropositivity, glomerular PLA2R, and IgG4-dominance/codominance significantly correlated with each other. The IgG4 subclass was rarely encountered in sMN. CONCLUSION: In our series, IgG4-dominance had the highest specificity in the differentiation of MN, just as high as that for anti-PLA2R seropositivity. The specificity values of PLA2R staining and IgG4-dominance/codominance with any IgG subclass or IgG4-dominance/IgG1-IgG4 codominance were ≤ 75%. Apart from IgG4 dominance, IgG4-dominance/IgG3-IgG4-codominance also had good statistical value in differentiating pMN from sMN. As IgG subclass switching during the progression of pMN was not the feature of our cohort, pMN in Hungarian patients is presumed to be an IgG4-related disorder right from the start. Although anti-PLA2R seropositivity has become the cornerstone for diagnosing pMN, if a kidney biopsy evaluation is conducted, besides the staining of PLA2R antigen, the evaluation of IgG subclasses provides relevant information for a differential diagnosis. Even in cases with IgG4-dominance, however, malignancy should be thoroughly checked.

Phenotype-Genotype Correlations in Three Different Cases of Adult-Onset Genetic Focal Segmental Glomerulosclerosis.

This study highlights the importance of a combined diagnostic approach in the diagnosis of rare diseases, such as adult-onset genetic FSGS. We present three adult patient cases evaluated with kidney biopsy for proteinuria, chronic kidney disease, and hypertension, which were suggestive of adult-onset genetic FSGS. Renal biopsy samples and formalin-fixed, paraffin-embedded fetal kidneys were evaluated using standard light microscopical stainings, direct immunofluorescence on cryostat sections, and electron microscopy. Clinical exome sequencing was performed for each case, and 45 FSGS-related genes were analyzed. Identifying mutations in the PAX2, ACTN4, and COL4A5 genes have prompted a re-evaluation of the previous histopathological examinations. The PAX2 mutation led to a thinner nephrogenic zone and decreased number of glomeruli, resulting in oligohydramnios during fetal development and oligomeganephronia and adaptive focal-segmental glomerulosclerosis in adulthood. The ACTN4 mutation caused distinct electron-dense aggregates in podocyte cell bodies, while the COL4A5 mutation led to segmental sclerosis of glomeruli with marked interstitial fibrosis and tubular atrophy. The identification of specific mutations and their histopathological consequences can lead to a better understanding of the disease and its progression, as well as potential treatment options.

Diffuse mesangial sclerosis in a PDSS2 mutation-induced coenzyme Q10 deficiency.

BACKGROUND: A 7-month-old male infant was admitted because he was suffering from nephrotic syndrome, along with encephalomyopathy, hypertrophic cardiomyopathy, clinically suspected deafness and retinitis pigmentosa, and an elevated serum lactate level. METHODS: Coenzyme Q10 supplementation was started because of the clinical suspicion of primary CoQ10 deficiency. Despite intensive efforts, he passed away 4 weeks after admission. RESULTS: The results of genetic tests, available postmortem, explored two hitherto undescribed mutations in the PDSS2 gene. Both were located within the polyprenyl synthetase domain. Clinical exome sequencing revealed a heterozygous missense mutation in exon 3, and our in-house joint-analysis algorithm detected a heterozygous large 2923-bp deletion that affected the 5 prime end of exon 8. Other causative defects in the CoQ10 and infantile nephrosis-related genes examined were not found. A postmortem histological, immunohistochemical, and electron microscopic evaluation of the glomeruli revealed collapsing-sclerosing lesions consistent with diffuse mesangial sclerosis. The extrarenal alterations included hypertrophic cardiomyopathy and diffuse alveolar damage. A histological evaluation of the central nervous system and skeletal muscles did not demonstrate any obvious abnormality. CONCLUSIONS: Until now, the clinical features and the mutational status of 6 patients with a PDSS2 gene defect have been reported in the English literature. Here, we describe for the first time detailed kidney morphology features in a patient with nephrotic syndrome carrying mutations in the PDSS2 gene.

Primary cardiac angiosarcoma: A case report.

Cardiac angiosarcomas are the most common primary malignant cardiac tumors in adults. The diagnosis is often delayed due to nonspecific clinical symptoms at presentation. The cornerstones of diagnosis are echocardiography and the histological evaluation of the cardiac biopsy. The knowledge on the treatment is limited; the outcomes of chemotherapy, radiotherapy, complete surgical removal, and heart transplantation are controversial. We report a 38-year-old woman with a primary heart tumor which infiltrated the right atrial wall and the pericardium and caused pericardial effusion. Angiosarcoma was verified histologically. The surgical excision could not be radical, and the patient died 3 months from diagnosis.

[Rapidly progressive proliferative glomerulonephritis with monoclonal immunoglobulin G deposits despite the mild histological changes. Case report]. / Enyhe szövettani eltérések ellenére gyors progressziójú proliferativ glomerulonephritis monoklonális immunglobulin-G-depozitumokkal.

Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits is characterized by granular deposits of monoclonal IgG; histologically it has typically a membranoproliferative or endocapillary pattern, and seen electronmicroscopically there are dense deposits without substructure. Here, we present the case of a 62-year-old Caucasian woman who was admitted with rapidly progressive kidney failure. The patient's status, the laboratory and imaging examinations did not support prerenal, postrenal and - among the intrinsic causes - vascular and tubulointerstitial origin. The proteinuria and dysmorphic microhematuria suggested rapidly progressive glomerulonephritis. Tests for anti-neutrophil cytoplasmic antibodies, anti-glomerular basement membrane, antinuclear antibodies and cryoglobulins were negative, the C3 and C4 levels were normal. The biopsy evaluation diagnosed proliferative glomerulonephritis with monoclonal IgG deposits because of mesangial granular deposits of IgG3-kappa, C3, and C1q, and ultrastructurally electron-dense deposits (incidence in our adult native kidney biopsy series: 0.18%). 31 glomeruli were assessed histologically. 29 glomeruli displayed mild mesangial hypercellularity, 2 glomeruli were globally sclerotic. Crescents were not observed. Mild arteriolar hyalinosis, interstitial fibrosis and tubular atrophy accompanied the glomerular alterations. In the postbiopsy evaluation, paraprotein or multiple myeloma was not detected. Despite the mild histological findings, the kidney failure progressed, and hemodialysis had to be started two weeks after the biopsy. Steroids, cyclophosphamide and rituximab did not affect her kidney function, and she remained on hemodialysis during the follow-up of 39 months. This report presents for the first time proliferative glomerulonephritis with monoclonal IgG deposits as the possible cause of rapidly progressive nephritic syndrome in the absence of pronounced glomerular proliferative, sclerotic or tubulointerstitial lesions. Orv Hetil. 2018; 159(38): 1567-1572.

Better understanding of transplant glomerulopathy secondary to chronic antibody-mediated rejection.

Transplant glomerulopathy (TG) is generally accepted to result from repeated episodes of endothelial activation, injury and repair, leading to pathological abnormalities of double contouring or multi-layering of the glomerular basement membrane. TG is a major sequel of chronic active antibody-mediated rejection (cABMR), from pre-existing or de novo anti-HLA antibodies. Hepatitis C infection, thrombotic microangiopathy or other factors may also contribute to TG development. TG prevalence is 5-20% in most series, reaching 55%, in some high-risk cohorts, and is associated with worse allograft outcomes. Despite its prevalence and clinical significance, few well-studied treatment options have been proposed. Similar to desensitization protocols, plasmapheresis with or without immunoabsorption, high-dose intravenous immunoglobulin, rituximab, bortezomib and eculizumab have been proposed in the treatment of TG due to cABMR individually or in various combinations. Robust clinical trials are urgently needed to address this major cause of allograft loss. This review summarizes the current knowledge of the epidemiology, etiology, pathology, and the preventive and treatment options for TG secondary to cABMR.

Recent advances in the investigation of pancreatic inflammation induced by large doses of basic amino acids in rodents.

It has been known for approximately 30 years that large doses of the semi-essential basic amino acid L-arginine induce severe pancreatic inflammation in rats. Recently, it has been demonstrated that L-arginine can also induce pancreatitis in mice. Moreover, other basic amino acids like L-ornithine and L-lysine can cause exocrine pancreatic damage without affecting the endocrine parenchyma and the ducts in rats. The utilization of these noninvasive severe basic amino acid-induced pancreatitis models is becoming increasingly popular and appreciated as these models nicely reproduce most laboratory and morphological features of human pancreatitis. Consequently, the investigation of basic amino acid-induced pancreatitis may offer us a better understanding of the pathogenesis and possible treatment options of the human disease.

The role of pancreatic ductal secretion in protection against acute pancreatitis in mice*.

OBJECTIVES: A common potentially fatal disease of the pancreas is acute pancreatitis, for which there is no treatment. Most studies of this disorder focus on the damage to acinar cells since they are assumed to be the primary target of multiple stressors affecting the pancreas. However, increasing evidence suggests that the ducts may also have a crucial role in induction of the disease. To test this hypothesis, we sought to determine the specific role of the duct in the induction of acute pancreatitis using well-established disease models and mice with deletion of the Na/H exchanger regulatory factor-1 that have selectively impaired ductal function. DESIGN: Randomized animal study. SETTING: Animal research laboratory. SUBJECTS: Wild-type and Na/H exchanger regulatory factor-1 knockout mice. INTERVENTIONS: Acute necrotizing pancreatitis was induced by i.p. administration of cerulein or by intraductal administration of sodium taurocholate. The pancreatic expression of Na/H exchanger regulatory factor-1 and cystic fibrosis transmembrane conductance regulator (a key player in the control of ductal secretion) was analyzed by immunohistochemistry. In vivo pancreatic ductal secretion was studied in anesthetized mice. Functions of pancreatic acinar and ductal cells as well as inflammatory cells were analyzed in vitro. MEASUREMENTS AND MAIN RESULTS: Deletion of Na/H exchanger regulatory factor-1 resulted in gross mislocalization of cystic fibrosis transmembrane conductance regulator, causing marked reduction in pancreatic ductal fluid and bicarbonate secretion. Importantly, deletion of Na/H exchanger regulatory factor-1 had no deleterious effect on functions of acinar and inflammatory cells. Deletion of Na/H exchanger regulatory factor-1, which specifically impaired ductal function, increased the severity of acute pancreatitis in the two mouse models tested. CONCLUSIONS: Our findings provide the first direct evidence for the crucial role of ductal secretion in protecting the pancreas from acute pancreatitis and strongly suggest that improved ductal function should be an important modality in prevention and treatment of the disease.

[A rare tubulopathy: Dent's disease in the background of focal segmental glomerular sclerosis]. / Ritka tubulopathia: Dent-betegség a focalis segmentalis glomerularis sclerosis hátterében.

Dent's disease is a proximal tubulopathy with heterogeneous genetical background. The typical clinical finding is characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis/nephrolithiasis and progressive chronic kidney failure. The underlying cause of the disease is the genetic defect (most commonly CLCN5 mutation) of the receptor-mediated endocytosis in the structure of proximal tubules. The typical fenotype may be composed of extrarenal symptoms. In the event of clinical suspicion, Dent's disease is only verifiable by genetic testing without the necessity of any kidney biopsy. The clinical case can be associated with nephrotic-range proteinuria or kidney failure as an indication of kidney biopsy. The number of articles available at scientific literatures on Dent's disease with the inclusion of renal histology is very slight. According to the pathophysiology of the highlighted Dent's disease and additionally to the expected tubular pathology, global or focal segmental glomerular sclerosis may apply for the majority of cases. Orv Hetil. 2023; 164(20): 788-791.

Collagen type IV nephropathy: genetic heterogeneity examinations in affected Hungarian families.

The Col4A3, Col4A4 and Col4A5 collagen type IV genes are found to be mutated in Col IV nephropathy. In males with a mutation in the Col4A5 gene (X-linked Alport syndrome: XL-AS), progressive renal disease always develops. Female carriers with a mutation in the Col4A5 gene can develop thin basement membrane nephropathy (TBMN). Males and females who carry 1 Col4A3 or Col4A4 mutation usually manifest TBMN with nonprogressive hematuria. In the event of 2 Col4A3 or Col4A4 gene mutations, the autosomal recessive AS will develop. We examined the cosegregation pattern of hematuria in 20 families. The renal biopsies led to diagnoses of AS in 7 families, and of TBMN in 6 families. In 7 others, the diagnosis of familial hematuria (FHU) was based on the clinical symptoms. Markers of the ColA3/Col4A4 and Col4A5 loci (Col4A3: CA11 and D2S401; Col4A4: HaeIII/RFLP; and Col4A5: DXS456, 2B6 and 2B20) were used to assess their linkage to the clinical symptoms and morphological alterations. Maximum likelihood and the FASTLINK version of the linkage program were applied to compute logarithm of the odds (LOD) scores. A linkage to the Col4A3/Col4A4 genes was identified in 5 families (FHU in 3, AS in 2 families, 25%, LOD score range: 0.20-3.51). The XL-AS pattern of inheritance seemed likely with Col4A5 in 9 families (45%, LOD: 0.43-4.20); we found 4 disease-causative mutations by high-resolution melting curve analysis (LC480) and sequencing in this group. In 2 FHU families, the linkage to chromosomes 2 and X was precluded. Knowledge of the genetic background of Col IV nephropathy is essential to avoid the misdiagnosis of FHU and early AS. The allele frequencies, heterozygosity content and polymorphism information content of the applied STR markers on unrelated Hungarian normal and affected chromosomes 2 and X were also calculated.

IgG4-Related Laryngeal Disease as a Possible Cause of Idiopathic Subglottic Stenosis: A Case Report.

INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory disorder. Laryngotracheal manifestation is very rare; therefore, it is usually associated with complex diagnostic and therapeutic problems. CASE REPORT: Herein, we report the case of a 35-year-old woman with idiopathic subglottic stenosis (ISGS) treated with one-step laryngotracheal reconstruction surgery. Postoperatively, the lesion was found to be a part of the IgG4-RD spectrum. Objective and subjective phoniatric tests, spirometry, and Quality of Life Questionnaire were used for the evaluation of postoperative functional results. Slide laryngotracheoplasty as a one-step surgery without stenting and tracheostomy ensured a sufficiently wide subglottic space with no adverse effect on voice quality. During a follow-up period of 22 months, endoscopy and computed tomography scan revealed no significant restenosis. The patient was able to return to premorbid activities of daily living without any further medical treatment. CONCLUSION: The laryngeal involvement of IgG4-RD is uncommon; however, it is a manifestation that should be included in the differential diagnosis of subglottic stenoses (SGS). Furthermore, subglottic IgG4-RD might be a potential etiological factor of ISGS and acquired airway stenosis after short-term intubation. Slide laryngotracheoplasty might be a favorable solution without stenting and tracheostomy even in special cases of SGS.

Pulmonary necrotizing sarcoid granulomatosis / A tüdo nekrotizáló sarcoid granulomatosisa.

Összefoglaló. A nekrotizáló sarcoid granulomatosis a granulomatosus pulmonalis angitisek közé tartozó, ritka kórkép. Egyesek a sarcoidosis variánsának, mások primer pulmonalis vasculitisnek tartják. A kórkép klinikai és patológiai jellegzetességeit két eset bemutatásával ismertetjük. A 20 éves nobeteg sürgosséggel került pulmonológiai osztályra száraz köhögés, jobb oldali, mély belégzéssel összefüggo mellkasi fájdalom és láz miatt, a 63 éves férfi beteget pedig pneumoniát követo kontroll-mellkasröntgenfelvételen látott elváltozás kivizsgálása során észlelték. Az autoimmun panel vizsgálata, a mikrobiológiai tesztek mindkét betegnél negatívnak bizonyultak, a légzésfunkciós vizsgálat és a bronchoszkópos vizsgálat nem talált eltérést. A mellkas-CT-felvételen lágyrész-denzitású nodulusok látszottak egyoldali dominanciával, a folyamatot nem kísérte a hilusi nyirokcsomók szimmetrikus megnagyobbodása. A nodulusok szövettani vizsgálata vált indokolttá, melyet videoasszisztált torakoszkópos tüdoreszekciós mintavétellel biztosítottak. Mikroszkóposan a tüdoparenchymában gócos nekrózisokat, a környezetükben el nem sajtosodó epitheloid sejtes granulomatosus gócokat, az átfutó artériákban pedig granulomatosus arteritist láttak; a klinikai adatok figyelembevételével a tüdo nekrotizáló sarcoid granulomatosisa diagnózisát állították fel. A tüdobetegség mindkét betegnél egy év alatt spontán regrediált. Az irodalom adatait és az eseteket összegezve, a tüdo nekrotizáló sarcoid granulomatosisában mikrobiológiai vizsgálatokkal nem igazolható tüdofertozés, és az immunológiai kivizsgálás sem tár fel szisztémás autoimmun betegséget; a diagnózis a klinikai kép és a képalkotó vizsgálatok alapján indikált szövettani vizsgálattal állítható fel. A betegség szteroidkezelésre jól reagál, de elofordul spontán regresszió is, az utóbbira láttunk példát. Bár az entitás átmenetet képez a nekrotizáló vasculitisek és a sarcoidosis között, egyre több érv szól amellett, hogy a sarcoidosis spektrumába tartozik. Orv Hetil. 2021; 162(38): 1541-1547. Summary. Necrotizing sarcoid granulomatosis is a rare entity currently classified as a subtype of granulomatous pulmonary angiitis. It is considered to be either a variant of sarcoidosis or a primary pulmonary angiitis. Two cases are demonstrated to present its clinical and pathological features. A 20-year-old female patient was admitted to the department of pulmonology with dry cough, right-sided chest pain during hyperventilation and fever. A 63-year-old male patient was observed with a right-sided lesion on chest X-ray after pneumonia. In both cases, autoimmune panel examination, microbiology tests, spirometry function test and bronchoscopy were unremarkable. Chest CT scans have revealed nodules with soft-tissue density without bilateral hilar lymphadenopathy. In order to clarify the diagnosis, video-assisted thoracoscopic resection (biopsy) was performed. Microscopically, parenchymal focal necrosis with adjacent to non-caseating granulomas and granulomatous angiitis were detected. In both cases, spontaneous remission occurred within a year. Histological examination - integrated with clinical data and radiological tests' results - is the gold standard form of evaluation to confirm necrotizing sarcoid granulomatosis; furthermore, exclusion of pneumonia and autoimmune diseases are also required. The disease responds well to corticosteroids; moreover, spontaneous remission is often reported, as it happened in both cases. Necrotizing sarcoid granulomatosis is a transition between necrotizing vasculitides and sarcoidosis; although more and more evidence appears supporting the fact that necrotizing sarcoid granulomatosis may belong to the spectrum of sarcoidosis. Orv Hetil. 2021; 162(38): 1541-1547.

"Dum spiro spero": clinicopathologic characteristics of SARS-CoV-2 infection / "Dum spiro spero": a SARS-CoV-2-fertozés klinikopatológiája 26 eset kapcsán.

Összefoglaló. Bevezetés: A kórboncolás hozzájárul a súlyos akut légzoszervi szindrómát okozó koronavírus-2 (SARS-CoV-2-) fertozés klinikopatológiai vonatkozásainak megismeréséhez. Célkituzés: A SARS-CoV-2-fertozöttek boncolása során gyujtött tapasztalatok bemutatása. Módszer: Egymást követoen boncolt, védooltásban nem részesült, SARS-CoV-2-fertozött elhunytak klinikai adatait, makro- és mikroszkópos észleleteit összegeztük; a tüdokimetszéseket SARS-CoV-2-nukleokapszid-immunfestéssel vizsgáltuk. Eredmények: A boncolást a halálok megállapítására (n = 14), tumorgyanú (n = 9), illetve törvényi kötelezettség (n = 3) miatt végeztük. A fertozést a klinikai észlelés vagy a boncolás során (n = 4) végzett SARS-CoV-2-nukleinsav-teszt igazolta. A tünetes betegség átlagos hossza 12,9 nap volt. 21 betegnél (medián életkor 69 év; 18 férfi) állt fenn COVID-19-pneumonia, mely 16 esetben önmagában, 4 esetben bakteriális pneumoniával vagy álhártyás colitisszel szövodve okozott halált; 1 antikoagulált pneumoniás beteg heveny retroperitonealis vérzésben halt meg. 3 betegnél a halált disszeminálódott malignus tumor, 1 betegnél coronariathrombosis, 1 mentálisan retardált betegnél pedig pulmonalis emboliás szövodmény okozta. A COVID-19-pneumoniás tüdok nehezek, tömöttek és vörösen foltozottak voltak. Szövettanilag a betegség idotartamától függoen diffúz alveolaris károsodás korai exsudativ vagy késobbi proliferativ fázisa látszott atípusos pneumocytákkal; gyakori volt a microthrombosis (n = 7), a macrothrombosis (n = 5), illetve a pulmonalis embolia (n = 4). A SARS-CoV-2-immunfestés pozitívnak bizonyult az esetek 38,5%-ában, dominálóan az exsudativ fázisban. Minden elhunyt társbetegség(ek)ben szenvedett, így magasvérnyomás-betegségben (n = 17), érelmeszesedésben (n = 14), 2-es típusú diabetesben (n = 8), rosszindulatú daganatban (n = 6), krónikus obstruktív tüdobetegségben (n = 4), elhízásban (n = 3), vesetranszplantáció utáni immunszuppresszióban (n = 3). Következtetés: Az irodalmi adatokkal összhangban, halálos COVID-19-pneumonia túlnyomóan idos, társbetegség(ek)tol sújtott férfiakban alakult ki. A boncolási gyakorlatban a SARS-CoV-2-nukleokapszid-immunfestéstol a diffúz alveolaris károsodás korai fázisában várható pozitivitás. Orv Hetil. 2021; 162(45): 1791-1802. INTRODUCTION: Autopsy is an important tool for the evaluation of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Objectice: The aim of this study was to present our experience with autopsies of patients diagnosed with SARS-CoV-2 infection. METHOD: Clinical data, macroscopic and microscopic findings of consecutive postmortems of non-vaccinated SARS-CoV-2 patients are summarized. Lung samples were evaluated with SARS-CoV-2 nucleocapsid immunohistochemistry. RESULTS: Autopsies were performed to determine the cause of death (n = 14), suspected tumours (n = 9) or due to legal obligation (n = 3). SARS-CoV-2 infection was verified by ante mortem (n = 22) and post mortem (n = 4) polymerase chain reaction. The mean duration of symptomatic disease was 12.9 days. Of 21 patients with COVID-19 pneumonia, 16 died of respiratory failure, 4 had additional bacterial pneumonia or Clostridioides difficile infection, and 1 developed hemorrhagic complication (n = 1). Other causes of death included disseminated malignancies (n = 3), coronary thrombosis (n = 1) and pulmonary embolism (n = 1). The affected lungs were heavy and had patchy red appearance. Exudative or proliferative phases of diffuse alveolar damage (DAD) were detected with atypical pneumocytes. Microthrombosis (n = 7), macrothrombosis (n = 5) and pulmonary embolism (n = 4) were frequent. The SARS-CoV-2 immunohistochemical reaction was positive in 38.5% of cases. All patients had co-morbidities, namely, hypertension (n = 17), atherosclerosis (n = 14), diabetes (n = 8), malignancies (n = 6), chronic obstructive pulmonary diseases (n = 4), obesity (n = 3) and immunosuppression after kidney transplantation (n = 3). CONCLUSION: Fatal COVID-19 pneumonia occurred mostly in elderly males with co-morbidities. In the autopsy practice, the SARS-CoV-2 nucleocapsid immunohistochemical reaction may confirm the infectious etiology in the early phase of DAD. Orv Hetil. 2021; 162(45): 1791-1802.

Variant Transthyretin Amyloidosis (ATTRv) in Hungary: First Data on Epidemiology and Clinical Features.

BACKGROUND: Variant transthyretin amyloidosis (ATTRv) is an autosomal dominant inherited disease, where the mutation of the transthyretin gene (TTR) results in the deposition of pathogenic protein fibrils in various tissues. The mutation type influences the clinical course. Until now, no data were available on the genotype, phenotype, and prevalence of Hungarian ATTRv patients. The aim of our study was to assess the prevalence, regional distribution, genotypes, and phenotypes of Hungarian patients with ATTRv. METHODS: With the collaboration of Hungarian regional and university centers, we identified patients diagnosed with ATTRv. We also searched prior publications for case studies of Hungarian ATTRv patients. RESULTS: 40 individuals in 23 families with ATTRv were identified within the borders of Hungary. At the time of the diagnosis, 24 of them were symptomatic. The two most common mutations were ATTRHis88Arg (nine families) and ATTRIle107Val (8 families). ATTRVal30Met was demonstrated in 2 families, and ATTRVal122del, ATTRPhe33Leu, ATTRIle84Ser, and ATTRAsp18Gly in one family each. The median age of the symptomatic patients at the time of clinical diagnosis was 65 years. The most common clinically significant organ involvement was restrictive cardiomyopathy, found in 24 patients. Polyneuropathy was diagnosed in 20 patients. A total of 19 patients showed a mixed phenotype. The leading symptom was heart failure in 8 cases (3 of them had only cardiac symptoms), polyneuropathy in 11 cases (all of them also had cardiac symptoms), and equally severe cardiac and neuropathy symptoms were present in 3 cases. Out of 24 symptomatic patients, 10 received targeted pharmacological therapy. The follow-up period ranged from 1 to 195 months. At the time of the retrospective analysis, 12 patients had already died, and 1 patient underwent heart transplantation. CONCLUSIONS: As TTR genotype influences the phenotype and clinical course of ATTRv, it is important to know the regional data. In Hungary, ATTRHis88Arg and ATTRIle107Val are the most common mutations in ATTRv, both presenting with mixed phenotype, but the median age at the time of the diagnosis is 9 years lower in patients with ATTRHis88Arg than in patients with ATTRIle107Val.

Kynurenic Acid and Its Analogue SZR-72 Ameliorate the Severity of Experimental Acute Necrotizing Pancreatitis.

The pathophysiology of acute pancreatitis (AP) is not well understood, and the disease does not have specific therapy. Tryptophan metabolite L-kynurenic acid (KYNA) and its synthetic analogue SZR-72 are antagonists of the N-methyl-D-aspartate receptor (NMDAR) and have immune modulatory roles in several inflammatory diseases. Our aims were to investigate the effects of KYNA and SZR-72 on experimental AP and to reveal their possible mode of action. AP was induced by intraperitoneal (i.p.) injection of L-ornithine-HCl (LO) in SPRD rats. Animals were pretreated with 75-300 mg/kg KYNA or SZR-72. Control animals were injected with physiological saline instead of LO, KYNA and/or SZR-72. Laboratory and histological parameters, as well as pancreatic and systemic circulation were measured to evaluate AP severity. Pancreatic heat shock protein-72 and IL-1ß were measured by western blot and ELISA, respectively. Pancreatic expression of NMDAR1 was investigated by RT-PCR and immunohistochemistry. Viability of isolated pancreatic acinar cells in response to LO, KYNA, SZR-72 and/or NMDA administration was assessed by propidium-iodide assay. The effects of LO and/or SZR-72 on neutrophil granulocyte function was also studied. Almost all investigated laboratory and histological parameters of AP were significantly reduced by administration of 300 mg/kg KYNA or SZR-72, whereas the 150 mg/kg or 75 mg/kg doses were less or not effective, respectively. The decreased pancreatic microcirculation was also improved in the AP groups treated with 300 mg/kg KYNA or SZR-72. Interestingly, pancreatic heat shock protein-72 expression was significantly increased by administration of SZR-72, KYNA and/or LO. mRNA and protein expression of NMDAR1 was detected in pancreatic tissue. LO treatment caused acinar cell toxicity which was reversed by 250 µM KYNA or SZR-72. Treatment of acini with NMDA (25, 250, 2000 µM) did not influence the effects of KYNA or SZR-72. Moreover, SZR-72 reduced LO-induced H2O2 production of neutrophil granulocytes. KYNA and SZR-72 have dose-dependent protective effects on LO-induced AP or acinar toxicity which seem to be independent of pancreatic NMDA receptors. Furthermore, SZR-72 treatment suppressed AP-induced activation of neutrophil granulocytes. This study suggests that administration of KYNA and its derivative could be beneficial in AP.

PAX2 Mutation-Related Oligomeganephronia in a Young Adult Patient.

Oligomeganephronic hypoplasia, commonly referred to as oligomeganephronia (OMN), is a rare pediatric disorder characterized by small kidneys. Histologically a paucity of nephrons is observed which show compensatory enlargement. Hyperfiltration injury leads to end-stage kidney disease. Here we report a 23-year-old Caucasian female patient who presented with a 7-year history of nonnephrotic proteinuria, slow worsening of renal function, normal-sized kidneys, normal blood pressure, healthy weight, and normoglycemia. Evaluation of a kidney biopsy specimen revealed sparsely distributed and markedly enlarged glomeruli (glomerular density 0.63/mm2, glomerular diameter 268 µm), focal segmental glomerulosclerosis (FSGS), and 70% effacement of the foot processes. The glomerular basement membrane was normal (mean thickness 285 nm). The genetic analysis of 19 genes known to cause FSGS identified a heterozygous de novo nonsense mutation of PAX2 in exon 4 (NM_003990.3:c.430C>T and NP_003981.2:p.Gln144Ter). Clinical investigations ruled out optic nerve coloboma, hearing loss, and vesicoureteral reflux. Magnetic resonance imaging of the urogenital tract found the uterus to be bicornuate. Based on these data, OMN in nonhypoplastic kidneys and adaptive FSGS related to PAX2 mutation was diagnosed. Her kidney function worsened during the 30-month follow-up (last visit: eGFR-EPI 32 mL/min/1.73 m2) despite angiotensin-converting enzyme inhibitor treatment. To our best knowledge, our patient is the seventh in the English-language literature with a biopsy diagnosis of OMN in an adult, the first observed with normal-sized kidneys, and the first in whom a specific etiologic genetic diagnosis was established. Nonsense PAX2 mutations between the paired domain and the octapeptide domain appear to manifest in renal-limited phenotype.

Immunohistochemical Analysis of a Vitreous Membrane Removed from a Patient with Incontinentia Pigmenti-Related Retinal Detachment.

This is a case history of a 23-year-old woman suffering from incontinentia pigmenti (IP). The patient's vision in the left eye started to deteriorate due to cataract progression at the age of 22, and by the age of 23, it dropped from 0.9 to 0.04. Ultrasound examination confirmed tractional vitreoretinal membranes. Vitrectomy was performed, therefore, on her left eye. The histological evaluation of vitreous membrane revealed a complex immunophenotype (positivity for glial fibrillary acidic protein (GFAP), vimentin, S-100, anti-pan cytokeratin antibody (AE/AE3), and smooth muscle-specific actin (SMA) to various extents). The right eye remained unsymptomatic throughout this course. Besides being the first to analyze the tractional vitreoretinal membrane in IP with immunohistochemical methods, this case study points out that extreme cases of asymmetric side involvement in IP do exist, even to the point of one eye being completely unsymptomatic.