Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis.

RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in DKC1, NOP10, or NHP2 cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males with DKC1 p.Glu206Lys and two children with homozygous NOP10 p.Thr16Met. Females with heterozygous DKC1 p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin-NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin-NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafish dkc1 mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.

Characterization of IL-19, -20, and -24 in acute and chronic kidney diseases reveals a pro-fibrotic role of IL-24.

BACKGROUND: Recently, the role of IL-19, IL-20 and IL-24 has been reported in renal disorders. However, still little is known about their biological role. METHODS: Localization of IL-20RB was determined in human biopsies and in the kidneys of mice that underwent unilateral ureteral obstruction (UUO). Renal Il19, Il20 and Il24 expression was determined in ischemia/reperfusion, lipopolysaccharide, streptozotocin, or UUO induced animal models of kidney diseases. The effects of H2O2, LPS, TGF-ß1, PDGF-B and IL-1ß on IL19, IL20 and IL24 expression was determined in peripheral blood mononuclear cells (PBMCs). The extents of extracellular matrix (ECM) and α-SMA, Tgfb1, Pdgfb, and Ctgf expression were determined in the kidneys of Il20rb knockout (KO) and wild type (WT) mice following UUO. The effect of IL-24 was also examined on HK-2 tubular epithelial cells and NRK49F renal fibroblasts. RESULTS: IL-20RB was present in the renal biopsies of patients with lupus nephritis, IgA and diabetic nephropathy. Amount of IL-20RB increased in the kidneys of mice underwent UUO. The expression of Il19, Il20 and Il24 increased in the animal models of various kidney diseases. IL-1ß, H2O2 and LPS induced the IL19, IL20 and IL24 expression of PBMCs. The extent of ECM, α-SMA, fibronectin, Tgfb1, Pdgfb, and Ctgf expression was lower in the kidney of Il20rb KO compared to WT mice following UUO. IL-24 treatment induced the apoptosis and TGF-ß1, PDGF-B, CTGF expression of HK-2 cells. CONCLUSIONS: Our data confirmed the significance of IL-19, IL-20 and IL-24 in the pathomechanism of renal diseases. Furthermore, we were the first to demonstrate the pro-fibrotic effect of IL-24.

An unusual complication of kidney biopsy: a case report.

BACKGROUND: The kidney biopsy is a routine procedure. Once an indication has been established, the benefit-risk balance may be considered. Sometimes, even with effective treatment, a severe complication may develop. CASE PRESENTATION: We present the case of a Caucasian 20-year-old young woman admitted to investigating and treating acute kidney injury. Renal involvement was characterized by kidney damage requiring hemodialysis treatment, positive immunologic testing, 0.5 g/day proteinuria, and microscopic hematuria. Contraindications were excluded, so an ultrasound-guided kidney biopsy was performed. To reduce the bleeding complication, Octostim (desmopressin) was administered. There were no direct complications following the kidney biopsy, so we continued the immunosuppressive treatment. Histologically founded thrombotic microangiopathy. However, 1 week later, severe bleeding developed with the need for urgent surgical left kidney removal. CONCLUSION: Kidney biopsy can be considered a routine procedure, and various bleeding episodes are most common in terms of complications, the detection of which is essential. Delayed bleeding complications are rare and can be caused by minor injuries. Our young patient had no injury during the hospitalization. We hypothesized that the developed serious and delayed bleeding complication resulted from effective immunosuppressive treatment. To the best of our knowledge, this is the first such case to date. However, renal biopsy in the case of thrombotic microangiopathy requires caution.

Kidney biopsy-based epidemiologic analysis shows growing biopsy rate among the elderly.

Systematic registration and examination of biopsy-related data in Central and Eastern Europe are scarce, while the health condition of the population is worse compared to other more developed countries. We aim to create a database and analyze the distribution and temporal variation of the renal biopsy diagnoses in Hungary, including the effect of the recent coronavirus pandemic. The diagnoses were standardized according to the recommendation of the European Renal Association. Native biopsy samples processed between January 1, 2006, and December 31, 2020, were analyzed. During the 15 years, 2140 native kidney biopsies were performed. The number of samples increased from 24.5 to 57.9 per million person-years and the median age from 37 to 51 years (p < 0.0001). The predominance of glomerular diseases was stable. The most frequent glomerulopathy was IgA nephropathy (21.5%), followed by focal segmental glomerulosclerosis (17.7%), and membranous nephropathy (15.7%). Trends showed the rise of ANCA-associated vasculitis. During the coronavirus pandemic, there was a decrease in the number of kidney biopsies and the proportion of membranous nephropathies. The diagnostic trends in our database showed increasing biopsy rates among the elderly and the growing frequencies of age-related diseases, which emphasizes the importance of altering medical focus according to demographic changes in this area.

Hypercalcemia and renal insufficiency ­ where can we start? / Hypercalcaemia és veseelégtelenség - merre induljunk?

Összefoglaló. Közleményünkben egy 63 éves férfi esetét ismertetjük, aki fáradékonyság, fogyás miatt végzett laboratóriumi vizsgálatokon igazolódó veseelégtelenség és hypercalcaemia miatt került felvételre Klinikánkra. A területen végzett röntgenvizsgálaton a koponyán frontalisan és a sacrumon csonteltérések (temporofrontalisan 13 mm-es, körülírtabb, mérsékelten intenzív árnyék és az S1-es rés sclerosisa) ábrázolódtak, ultrahangvizsgálat során lépmegnagyobbodás volt látható. Tünetei hátterében endokrin vagy malignus betegség nem igazolódott. A háttérben elsosorban myeloma multiplex merült fel, ugyanakkor azt célzott vizsgálatokkal sem megerosíteni, sem kizárni nem lehetett, így csontvelo-biopszia történt. A vesefunkció-romlás okának tisztázása végett vesebiopsziát végeztünk, melynek elozetes eredménye interstitialis nephritist véleményezett óriássejtekkel. Az angiotenzinkonvertáló enzim szérumszintjének ez okból történo vizsgálata emelkedett szintet mutatott, így esetünket Boeck-sarcoidosis extrapulmonalis manifesztációjának tartottuk. Per os szteroidkezelésre a beteg tünetei egyértelmu regressziót mutattak. A csontvelo- és vesebiopszia eredménye megerosítette a Boeck-sarcoidosis diagnózisát. A sarcoidosis ezen extrapulmonalis formája hypercalcaemiával és veseérintettséggel - de tüdoérintettség nélkül - rendkívül ritka, különös tekintettel a vesét érinto formára. Hypercalcaemia nagyjából 7,9%-ban, veseelégtelenség 1,4%-ban fordul elo. Ezen eset alapján fontos hangsúlyozni, hogy a hypercalcaemia és a veseelégtelenség hátterében a gyakoribb endokrin, malignus, hematológiai okok mellett a Boeck-sarcoidosisnak is fel kell merülnie a differenciáldiagnosztika során. Orv Hetil. 2021; 162(13): 514-518. Summary. We present the case of a 63-year-old male patient who was admitted to our Clinic with fatigue, weight loss, hypercalcemia, renal insufficiency and anemia. X-ray showed lesions on the frontal skull and sacral region. On abdominal ultrasound, splenomegaly was detected. Based on these, myeloma multiplex was the most likely initial diagnosis; this, however, could not be confirmed with targeted serum tests, therefore bone marrow biopsy was performed. To clarify the underlying cause of decreased kidney function, renal biopsy was performed, the preliminary results of which revealed interstitial nephritis accompanied by giant cells. Serum angiotensin converting enzyme level was elevated, which led to the diagnosis of Boeck sarcoidosis with extrapulmonary manifestations. Oral corticosteroid therapy was commenced that was followed by regression of the patient's symptoms and laboratory abnormalities. Both the bone marrow and the kidney biopsies supported the diagnosis of Boeck sarcoidosis. Presentation of sarcoidosis with hypercalcemia and renal insufficiency but without the involvement of the lungs is extremely rare. Hypercalcemia occurs in about 7.9% and renal insufficiency in 1.4% of the cases. Based on this case, it is important to highlight that in the background of hypercalcemia and renal failure - beside the more frequent causes such as endocrine and hematological diseases, malignancy - one is to consider the possibility of Boeck sarcoidosis as well. Orv Hetil. 2021; 162(13): 514-518.

Increased synthesis of vascular endothelial growth factor in allergic airway inflammation in histidine decarboxylase knockout (HDC(-/-)) mice.

Histamine and vascular endothelial growth factor (VEGF) have been implicated in the pathogenesis of allergic asthma; they enhance inflammation, vascular permeability, and mucus secretion. Histamine was suggested to alter the level of VEGF via the H2 receptors. Here the authors have applied histidine decarboxylase gene-targeted (HDC(-/-)) mice, lacking histamine, to investigate the effect of histamine deficiency on VEGF expression in an animal model of asthma. HDC(-/-) and wild-type (WT) mice were sensitized and challenged with ovalbumin (OVA). VEGF mRNA expression and protein level were determined in the lung. Number of VEGF-positive immune cells of bronchoalveolar lavage (BAL) and their intracellular VEGF content were measured by flow cytometry. VEGF protein level in the lung and in the BAL cells was increased in OVA treated (HDC(-/-)(ova) as well as in WT(ova)) animals compared to their controls. However, there was no difference in the VEGF levels between HDC(-/-) or WT animals, either in the lung or in the BAL cells. In conclusion, increased VEGF production of the lung or BAL immune cells can be induced by allergen provocation independently from the genetic background of the animals. These data suggest that VEGF-mediated allergic processes can persist in the absence of histamine.

Renal ultrafiltration changes induced by focused US.

PURPOSE: To determine if focused ultrasonography (US) combined with a diagnostic microbubble-based US contrast agent can be used to modulate glomerular ultrafiltration and size selectivity. MATERIALS AND METHODS: The experiments were approved by the animal care committee. The left kidney of 17 healthy rabbits was sonicated by using a 260-kHz focused US transducer in the presence of a microbubble-based US contrast agent. The right kidney served as the control. Three acoustic power levels were applied: 0.4 W (six rabbits), 0.9 W (six rabbits), and 1.7 W (five rabbits). Three rabbits were not treated with focused US and served as control animals. The authors evaluated changes in glomerular size selectivity by measuring the clearance rates of 3000- and 70,000-Da fluorescence-neutral dextrans. The creatinine clearance was calculated for estimation of the glomerular filtration rate. The urinary protein-creatinine ratio was monitored during the experiments. The authors assessed tubular function by evaluating the fractional sodium excretion, tubular reabsorption of phosphate, and gamma-glutamyltransferase-creatinine ratio. Whole-kidney histologic analysis was performed. For each measurement, the values obtained before and after sonication were compared by using the paired t test. RESULTS: Significant (P < .05) increases in the relative (ratio of treated kidney value/nontreated kidney value) clearance of small- and large-molecule agents and the urine flow rates that resulted from the focused US treatments were observed. Overall, 1.23-, 1.23-, 1.61-, and 1.47-fold enhancement of creatinine clearance, 3000-Da dextran clearance, 70 000-Da dextran clearance, and urine flow rate, respectively, were observed. Focal tubular hemorrhage and transient functional tubular alterations were observed at only the highest (1.7-W) acoustic power level tested. CONCLUSION: Glomerular ultrafiltration and size selectivity can be temporarily modified with simultaneous application of US and microbubbles. This method could offer new opportunities for treatment of renal disease.

Opposite prognostic roles of HIF1α and HIF2α expressions in bone metastatic clear cell renal cell cancer.

BACKGROUND: Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1α/HIF2α and their selected target genes in primary tumors and corresponding bone metastases. RESULTS: Expression of HIF2α was lower in mRCC both at mRNA and protein levels (p/mRNA/=0.011, p/protein/=0.001) while HIF1α was similar to nmRCC. At the protein level, CAIX, GAPDH and GLUT1 were increased in mRCC. In all primary RCCs, low HIF2α and high HIF1α as well as CAIX, GAPDH and GLUT1 expressions correlated with adverse prognosis, while VEGFR2 and EPOR gene expressions were associated with favorable prognosis. Multivariate analysis confirmed high HIF2α protein expression as an independent risk factor. Prognostic validation of HIFs, LDH, EPOR and VEGFR2 in RNA-Seq data confirmed higher HIF1α gene expression in primary RCC as an adverse (p=0.07), whereas higher HIF2α and VEGFR2 expressions as favorable prognostic factors. HIF1α/HIF2α-index (HIF-index) proved to be an independent prognostic factor in both the discovery and the TCGA cohort. PATIENTS AND METHODS: Expressions of HIF1α and HIF2α as well as their 7 target genes were analysed on the mRNA and protein level in 59 non-metastatic ccRCCs (nmRCC), 40 bone metastatic primary ccRCCs (mRCC) and 55 corresponding bone metastases. Results were validated in 399 ccRCCs from the TCGA project. CONCLUSIONS: We identified HIF2α protein as an independent marker of the metastatic potential of ccRCC, however, unlike HIF1α, increased HIF2α expression is a favorable prognostic factor. The HIF-index incorporated these two markers into a strong prognostic biomarker of ccRCC.

Chlamydia pneumoniae in coronary bypass grafts of redo patients. The concept of the 'adventitial baseline infection'.

The pathogenic role of Chlamydia pneumoniae in late coronary bypass graft failure has not yet been extensively investigated. We examined failed and new arterial/venous bypass grafts using immunohistochemistry, polymerase chain reaction (PCR), and serology. Thirty-four long-term failed grafts and 28 new grafts were examined in 21 patients undergoing redo coronary artery bypass grafting (CABG). Immunohistochemically, 28 (82%) failed grafts were positive in the intimal-medial compartment, and 33 grafts (97%) were positive for C. pneumoniae in the adventitia. Thirteen (46%) and 27 (96%) new grafts showed infection in the intima-media and in the adventitia, respectively (p < 0.05). Immunohistochemically, the overall presence of C. pneumoniae in all vessels examined was 66% in the intima-media and 97% in the adventitia (p < 0.05). C. pneumoniae was detected by PCR in 19 (31%) of all the vessels examined. C. pneumoniae seems to be frequently present in grafts of patients considered for redo CABG in Hungary. The adventitia of both failed, and new grafts particularly often contained C. pneumoniae. The results suggest that there exists an adventitial baseline infection from which infection of the inner wall layers develops, depending on local microenvironmental conditions. This is the first study to evaluate chlamydial infection in arterial/venous coronary grafts by immunohistochemistry, PCR, and serology.

Sudden death due to infiltration of left bundle branches by interventricular septal cardiac fibroma.

Cardiac fibromas are benign conditions; however, their location and size may cause ventricular arrhythmias and sudden cardiac death. We report a case of a 68-year-old female who died suddenly. Postmortem investigation detected a huge cardiac fibroma in the pars muscularis of the interventricular septum, occupying almost the entire muscular septum, and restricting the volume of left ventricular chamber. Histological examination revealed numerous foci of calcification in the alternating complex interlacing or strictly parallel collagenous fiber mass. Tumor mass was mainly demarcated, but in some places, fibrous infiltration of surrounding working cardiac muscle was found. We present a case when direct tumor involvement in the descending left bundle branches was evidenced. Mainly, the branches of septal fascicle were disrupted, entrapped, and degenerated by the tumor mass. This case report emphasizes that postmortem histological examination of conduction system in all sudden cardiac death cases may substantially improve the accuracy of postmortem diagnosis.

Expression and function of C5a receptor in a fatal anaphylaxis after honey bee sting.

The mechanisms leading to death from anaphylaxis after insect sting involve antigen cross-linkage of antibody molecules that activate immunoglobulin receptors on inflammatory cells. The aim of our study was to investigate the pathomorphology and the expression of C5aR in fatal anaphylaxis in a patient after a fatal insect sting. A 38-year-old women was stung by a honeybee. C5R1 expression was detected in many dilated capillaries in the lungs. Pulmonary epithelial cells did not bind the monoclonal antibody for C5R1; however, intensive cytoplasmic staining was detected in endothelial cells. The findings of this case provide evidence for an active role of complement in fatal anaphylaxis elicited by bee venom. C5aR detection could be useful in the identification of sudden death cases because of unwitnessed fatal insect sting cases. Authors can recommend this immunohistochemical analysis on all sudden unexpected deaths outdoors where a possible bee sting might occur.

Prognostic factors and survival of renal clear cell carcinoma patients with bone metastases.

In our retrospective study the pathological and clinical factors, influencing the survival of 65 renal clear cell carcinoma patients operated for bone metastasis between 1990 and 2008 were examined. Based on Kaplan-Meier curves age, gender, clinical symptoms, pathological fracture, progression to the soft tissues, localization and size of the metastasis, whether the occurrence of multiplex metastases is multiorganic or only located to the skeletal system and the stage and grade of primary renal cancer did not influence the survival. The survival significantly improved if the bone metastases were solitary, low Fuhrman grade, late onset; and radical surgery was performed. Based on Cox regression analysis, survival after bone surgery was influenced by the multiplicity and grade of metastasis and by the radicality of the surgery, whereas survival after nephrectomy was significantly influenced by onset time and grade of metastasis. When the solitary metastasis was radically removed, 75.0% of the patients survived the first, and 35.5% the fifth postoperative year. If the metastasis was multiple or the surgery was not radical, no patient survived the fifth year. This is the first report on the prognostic significance of the Fuhrman grade of bone metastasis of renal cell cancer. While the Fuhrman grade of the primary tumour did not influence the survival, the lower grade of metastasis was associated with a significant longer survival. Therefore in cases of solitary, operable, late onset metastases with low Fuhrman grade radical removal is recommended, since this way in 35.5% of cases 5 year survival can be expected.

Fatal asphyxia due to laryngomucocele.

Laryngocele is a rare benign lesion of the larynx resulting from an abnormal dilation of the laryngeal saccule, however, severe airway obstruction and even asphyxia may occur. We report the case of a 55-year-old woman who presented with a feeling of discomfort and mild asphyxia. There was a smooth, firm swelling, 2 cm in diameter, upon palpation on the right side of the neck. Laryngoscopy revealed a bulging near the ventricular and right aryepiglottic folds. CT scan, MRI investigation and in-hospital observation were suggested, the patient, however, refused acute treatment and hospitalization and died suddenly, a few minutes after leaving. Autopsy revealed combined laryngocele with internal and external components. As the presented case shows, the internal part of the laryngocele may cause rapid and complete obstruction. The examining physician should therefore call the patient's attention to this potential life threatening condition.

Fatal renal hemorrhage after extracorporeal shock wave lithotripsy.

Renal hematoma is one of the most severe complications of extracorporeal shock wave lithotripsy (ESWL). ESWL is used in the noninvasive treatment of urinary calculosis. The shock waves can lead to capillary damage, renal parenchymal or subcapsular hemorrhage. We present a case with fatal complication and the result of the medico-legal evaluation. A 71-year-old woman was treated by ESWL, renal hematoma was detected during the clinical observation, and the patient died. The death occurred despite close clinical observation as a consequence of a rare complication of ESWL. The mechanism of death was hemorrhagic hypovolemic shock due to renal hemorrhage complications due to ESWL for treatment of renal calculi. This therapeutic complication is a known complication of appropriate treatment.

Suicidal hanging on high-voltage line pylon.

Hanging is one of the most frequent methods for suicides among young males. This report presents two cases of suicide by hanging on pylons carrying high-voltage power lines. The male victims suffered electrocution while committing suicide. Electrocution was the cause of death in both cases, however in one case blunt force injuries from hanging contributed to death. In these two cases hanging was the intentional method of suicide and it was followed by electrocution. The cases demonstrate that scene investigation, a detailed autopsy with histology, and amamnestic data are essential in the evaluation of suicides by hanging and that the determination of the cause of death remains a challenge in investigating such cases.