Comprehensive Investigation of Angiogenesis, PASS Score and Immunohistochemical Factors in Risk Assessment of Malignancy for Paraganglioma and Pheochromocytoma.

A challenging task in routine practice is finding the distinction between benign and malignant paragangliomas and pheochromocytomas. The aim of this study is to conduct a comparative analysis of angiogenesis by assessing intratumoral microvascular density (MVD) with immunohistochemical (IHC) markers (CD31, CD34, CD105, ERG), and S100 immunoreactivity, Ki67 proliferative index, succinate dehydrogenase B (SDHB) expressiveness, tumor size with one the most utilized score Pheochromocytoma of Adrenal Gland Scales Score (PASS), using tissue microarray (TMA) with 115 tumor samples, 61 benign (PASS < 4) and 54 potentially malignant (PASS ≥ 4). We found no notable difference between intratumoral MVD and potentially malignant behavior. The group of potentially malignant tumors is significantly larger in size, has lower intratumoral MVD, and a decreased number of S100 labeled sustentacular cells. Both groups have low proliferative activity (mean Ki67 is 1.02 and 1.22, respectively). Most tumors maintain SDHB expression, only 6 cases (5.2%) showed a loss of expression (4 of them in PASS < 4 group and 2 in PASS ≥ 4). PASS score is easily available for assessment and complemented with markers of biological behavior to complete the risk stratification algorithm. Size is directly related to PASS score and malignancy. Intratumoral MVD is extensively developed but it is not crucial in evaluating the malignant potential.

Risk factors for postoperative acute kidney injury after major abdominal surgery.

AIM: Acute kidney injury (AKI) worsens the outcome in a significant number of hospitalized patients. Risk models mainly address cardiac surgery, while significantly less attention is paid to AKI after major abdominal surgery (MAS). This study aims to evaluate the incidence, along with risk factors, and intrahospital outcomes of AKI after MAS. MATERIAL AND METHODS: Our retrospective study included 200 adult patients treated with MAS (in the same institution). Exclusion criteria were obstructive nephropathy, contrast-induced nephropathy, and dialysis dependence whether due to end-stage renal disease (ESRD) or AKI before MAS. Data on preoperative, intraoperative, as well as postoperative variables were collected from patients' medical history and electronic medical records. RESULTS: AKI was diagnosed in 33 (16.5%) patients, with 2 patients treated with hemodialysis. The multivariate logistic regression model showed that the number of intraoperative blood transfusions (p = 0.01), pneumonia (p < 0.001), and vasoactive drug use (p = 0.02) were independently associated with postoperative AKI. Each blood transfusion administered increased the risk of developing AKI by 1.41, vasoactive drug use by 4.13, and the risk of AKI in those with pneumonia was 15.32 times higher. The lethal outcome was observed significantly more frequently in patients with AKI (39.4 vs. 4.8%, p < 0.001). CONCLUSION: Identification of independent predictors of AKI after MAS such as the number of transfusions during surgery, sepsis, pneumonia, and the need for vasoactive drug therapy could help prevent AKI and lower the probability of lethal outcomes after MAS.

Association of multiple retinal nodular hamartomas and "confetti" skin lesions with end-stage renal disease in patients with tuberous sclerosis.

PURPOSE: The main purpose of this study is to explore characteristics of patients with chronic kidney disease in tuberous sclerosis (TSC) and to underline differences in clinical characteristics between end-stage renal disease (ESRD) patients and patients in earlier stages of chronic kidney disease. METHODS: This multicentric, retrospective study included data for 48 patients from seven South-Eastern European countries (Albania, Bosnia and Herzegovina, Croatia, Greece, Montenegro, Serbia, Slovenia) in the period from February to August 2020. Researchers collected data from local and national nephrological and neurological registries and offered clinical and laboratory results from medical histories in follow-up periods. RESULTS: This study enrolled 48 patients with a median age of 32.3 years (range, 18-46 years), and predominant female gender (60.45%). The percentage of patients with chronic kidney disease (CKD) diagnosis of the total number of patients was 66.90%, with end-stage renal disease development in 39.6%. The most prevalent renal lesions leading to chronic kidney disease were angiomyolipomas (AMLs) in 76.6%, while multiple renal cysts were present in 42.6% of patients. Nephrectomy was performed in 43% of patients, while the mTOR inhibitors were used in 18 patients (37.5%). The majority of patients had cutaneous manifestations of tuberous sclerosis-83.30% had hypomelanotic cutaneous lesions, and 68.80% had angiofibromas. Multiple retinal nodular hamartomas and "confetti" skin lesions were more frequent in end-stage renal disease (ESRD) than in patients with earlier stages of chronic kidney disease (p-0.033 and 0.03, respectively). CONCLUSION: Our study has also shown that retinal hamartomas and "confetti" skin lesions are more frequent in end-stage renal diseases (ESRD) patients than in other chronic kidney disease (CKD) patients. Usage of mTOR inhibitors can also reduce the number of complications and associated with tuberous sclerosis, such as dermatological manifestations and retinal hamartoma, which are more common in the terminal stage of chronic kidney disease.

A Study on Mortality Predictors in Hemodialysis Patients Infected with COVID-19: Impact of Vaccination Status.

The global outbreak of COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has prompted significant public health concerns. This study focuses on 442 chronic hemodialysis patients diagnosed with COVID-19, emphasizing the impact of vaccination status on clinical outcomes. The study investigates the correlation between vaccination status and laboratory findings, aiming to identify predictive factors for mortality. Results indicate that vaccination status plays a crucial role in outcomes. Full vaccination, evidenced by two or three doses, is associated with better outcomes, including reduced incidence of bilateral pneumonia and lower risks of complications such as hemorrhage and thrombosis. Laboratory analyses reveal significant differences between vaccinated and unvaccinated patients in parameters like C-reactive protein, ferritin, and white blood cell counts. Univariate and multivariate Cox proportional hazards regression analyses identify several factors influencing mortality, including comorbidities, pneumonia development, and various inflammatory markers. In conclusion among hemodialysis patients affected by COVID-19 infection, vaccination with at least three doses emerges as a protective factor against fatal outcomes. Independent predictors of mortality are CRP levels upon admission, maximum CRP values during the illness and cardiovascular comorbidities. Noteworthy lymphocytopenia during infection exhibits a notable level of specificity and sensitivity in predicting mortality.

Influence of Pretransplant Factors on Posttransplant Anemia Recovery Rate in Primary Deceased Donor Kidney Transplant Recipients.

OBJECTIVES: Our objective was to evaluate the influence of pretransplant risk factors on posttransplant anemia recovery. MATERIALS AND METHODS: This single-center observational retrospective study included 80 deceased donor kidney transplant recipients who had been followed up to 16 months after kidney transplant. Time point of posttransplant anemia recovery was considered the time when hemoglobin of 11.0 g/dL was achieved and maintained for 3 consecutive monthly visits. We collected donor/transplant characteristics (age, sex, hypertension history, cause of death, donor kidney function, expanded criteria donor status, deceased donor score, HLA mismatch, and cold ischemia time) and recipient data (pretransplant hemoglobin, parathyroid hormone, kidney graft function, delayed graft function, acute rejection, infections, surgical bleeding, posttransplant parathyroid hormone, iron stores, and C-reactive protein and tacrolimus levels). We used univariate and multivariate Cox proportional hazards analyses and Kaplan-Meier plots to determine associations between variables and posttransplant anemia recovery rate. P < .05 was considered significant. RESULTS: We identified 62 deceased donors (33 male; mean age 50 ± 15.1 years) and 80 kidney transplant recipients (52 male; mean age 47.0 ± 10.6 years). Mean pretransplant hemoglobin was 11.4 ± 1.5 g/dL. Donor age, deceased donor score, pretransplant parathyroid hormone, posttransplant transferrin saturation (all P < .05), and tacrolimus level (P < .01) were significantly related to posttransplant anemia recovery. Kaplan-Meier curve identified that recipients of deceased donors below 60 years old achieved hemoglobin of 11.0 g/dL more frequently and earlier than recipients of deceased donors above 60 years old (P < .05). CONCLUSIONS: Deceased donor age, deceased donor score, pretransplant serum parathyroid hormone, posttransplant transferrin saturation, and tacrolimus level were significantly associated with posttransplant anemia recovery rate in deceased donor kidney transplant recipients. Anemia recovery was more frequent and earlier in recipients of deceased donors below 60 years than in recipients of donors 60 years old and above.

The importance of MDR1 gene polymorphisms for tacrolimus dosage.

Polymorphisms of the multi drug resistance (MDR1) gene cause variability in P-glycoprotein mediated metabolism of tacrolimus. The aim of this study was to examine the relationship between MDR1 gene single nucleotide polymorphisms (SNPs) and their haplotypes with dosage of tacrolimus in kidney transplant recipients who were cytochrome (CYP) 3A5*3 homozygotes. This study included 91 kidney transplant recipients followed two years after transplantation. Detection and analysis of MDR1 gene polymorphisms in positions C1236T, G2677T/A and C3435T were performed using PCR method. Patients with variant alleles for SNPs G2677T/A and C3435T required higher doses of tacrolimus and had a lower level/dose (L/D) ratio than patients with wild alleles or heterozygotes. That difference was the most obvious for SNP G2677T/A where TT homozygotes required significantly higher doses of tacrolimus during whole follow-up. Their L/D was significantly lower in the first month after transplantation. Recipients with CTT/TTT haplotype also had lower L/D than those with CGC/TTT and CGC/CGC, significantly in the 10th and 20th days after transplantation respectively (p<0.05). Our results demonstrate that TT homozygotes at positions G2677T/A and C3435T required a higher tacrolimus dose than those with wild alleles or heterozygotes. It may be helpful in the prevention of tacrolimus nephrotoxicity early after transplantation.

Early post-transplant lymphoproliferative disorder ­ Case of fatal lymphoma after kidney transplantation.

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a common malignancy following organ transplantation. Risk for PTLD is associated with the use of anti-thymocyte globulin in the prevention and treatment of acute rejection following kidney transplantation. Case Outline: We report a case of fatal PTLD presented with sudden onset of fever. A 33-year-old male patient with primary diagnosis of left kidney agenesia underwent kidney transplantation six years following hemodialysis treatment initiation. Deceased donor was a 66-year-old female whose cause of death was cerebrovascular accident. Immunosuppressive regimen consisted of basiliximab, corticosteroids, tacrolimus, and mycophenolate mofetil. Six months upon transplantation the patient was hospitalized due to fever of unknown origin. All microbiological samples were negative, but abdominal ultrasound revealed round solid mass in the right native kidney. Right nephrectomy was performed showing tumor 35 × 35 × 20 mm in size within the 70 × 40 × 35 mm kidney. Pathohistological analysis confirmed very rare monomorphic B-cell PTLD ­ B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. Conclusion: We consider this case of PTLD following kidney transplantation particular because of the tumor mass in native kidney after basiliximab induction and rare pathohistology. In a transplanted patient with fever, PTLD must always be considered, irrespective of immunosuppressive regimen.

[High rate of native arteriovenous fistulas: how to reach this goal?].

The types of vascular accesses for hemodialysis (HD) include the native arteriovenous fistula (AVF), arteriovenous graft (AVG) and central venous catheter (CVC). Adequately matured native AVF is the best choice for HD patients and a high percentage of its presence is the goal of every nephrologist and vascular surgeon. This paper analyses the number and type of vascular accesses for HD performed over a 10-year period at the Clinical Center of Serbia, and presents the factors of importance for the creation of such a high number of successful native AVF (over 80%). Such a result is, inter alia, the consequence of the appointment of the Vascular Access Coordinator, whose task was to improve the quality of care of blood vessels in the predialysis period as well as of functional vascular accesses, and to promote the cooperation among different specialists within the field. Vascular access is the "lifeline"for HD patients. Thus, its successful planning, creation and monitoring of vascular access is a continuous process that requires the collaboration and cooperation of the patient, nephrologist, vascular surgeon, radiologist and medical personnel.

Assessment of oxidative status in patients with acute kidney injury: a pilot study.

Extensive experimental evidence confirms the role of oxidative stress as a major contributor to the pathogenesis of acute kidney injury (AKI). However, less information is available on the evolution of prooxidant-antioxidant parameters from early to end-phase renal function decline in humans. This study aimed to determine the oxidative status in dynamic throughout the evolutionary phases of the disease. The study included patients with cardiovascular pathology and AKI hospitalized in the intensive care unit (n = 69) and age-matched healthy controls (n = 30). They were followed through three phases of AKI; the first [corrected] phase was the phase of diagnosis, which is characterized by oliguria/anuria, the [corrected] second phase was established diuresis, and the [corrected] third phase was the polyuric phase. In these phases of the disease, blood samples were taken from the patients for biochemical analysis. From the collected whole blood, we measured spectrophotometrically prooxidants: index of lipid peroxidation, measured as Thiobarbituric acid reactive substances (TBARS), nitrite (NO2⁻), superoxide anion radical (O2⁻) and hydrogen peroxide (H2O2), and antioxidants: activity of superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH) from erythrocyte lysate. Comparing the results of the three measurements, a significant difference was found in the levels of NO2⁻ and GSH, both of which increased in the second phase (P < 0.05) and then decreased in the third phase, and a significant increase in TBARS, which was elevated in the second phase (P < 0.05) and did not change significantly until the third phase. Our results showed phase-dependent modification in 3 parameters of the oxidative status (TBARS, NO2⁻ and GSH). Whether these changes contribute to the deterioration of renal function in AKI remains to be established.

Dialysis headache in patients undergoing peritoneal dialysis and hemodialysis.

OBJECTIVES: Headache is among most frequently encountered neurological symptom during hemodialysis (HD), but still under investigated in peritoneal dialysis (PD) patients. The aim of this study was to assess the incidence and clinical characteristics of dialysis headache (DH) in HD and PD patients. MATERIAL AND METHODS: A total of 409 patients (91 on PD and 318 on HD) were interviewed using a structured questionnaire, designed according to the diagnostic criteria of the International Headache Classification of Headache Disorders from 2004. Patients with DH underwent a thorough neurological examination. RESULTS: DH was reported by 21 (6.6%) HD patients and 0 PD patients. PD patients had significantly lower serum sodium, potassium, calcium, phosphate, urea and creatinine, calcium-phosphate product, and diastolic blood pressure than HD patients. HD patients had significantly lower hemoglobin compared to PD patients. Primary renal disease was mostly parenchymal in HD patients, and vascular in PD patients. DH appeared more frequently in men, mostly during the third hour of HD. It lasted less than four hours, was bilateral, non-pulsating and without associated symptoms. CONCLUSION: Biochemical alterations may be implicated in the pathophysiology of DH. Specific features of DH might contribute to better understanding of this secondary headache disorder.

Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α1 GABA(A) receptors.

Despite significant advances in understanding the role of benzodiazepine (BZ)-sensitive populations of GABAA receptors, containing the α1, α2, α3 or α5 subunit, factual substrates of BZ-induced learning and memory deficits are not yet fully elucidated. It was shown that α1-subunit affinity-selective antagonist ß-CCt almost completely abolished spatial learning deficits induced by diazepam (DZP) in the Morris water maze. We examined a novel, highly (105 fold) α1-subunit selective ligand-WYS8 (0.2, 1 and 10 mg/kg), on its own and in combination with the non-selective agonist DZP (2 mg/kg) or ß-CCt (5 mg/kg) in the water maze in rats. The in vitro efficacy study revealed that WYS8 acts as α1-subtype selective weak partial positive modulator (40% potentiation at 100nM). Measurement of concentrations of WYS8 and DZP in rat serum and brain tissues suggested that they did not substantially cross-influence the respective disposition. In the water maze, DZP impaired spatial learning (acquisition trials) and memory (probe trial). WYS8 caused no effect per se, did not affect the overall influence of DZP on the water-maze performance and was devoid of any activity in this task when combined with ß-CCt. Nonetheless, an additional analysis of the latency to reach the platform and the total distance swam suggested that WYS8 addition attenuated the run-down of the spatial impairment induced by DZP at the end of acquisition trials. These results demonstrate a clear difference in the influence of an α1 subtype-selective antagonist and a partial agonist on the effects of DZP on the water-maze acquisition.

Behavioural characterization of four endemic Stachys taxa.

We performed a basic behavioral characterization of methanol extracts of four Balkan endemic Stachys taxa: S. anisochila (SA), S. beckeana (SB), S. plumosa (SP) and S. alpina subsp. dinarica (SAD). The behavioral activity of extracts dosed intraperitoneally in the range 100-400 mg/kg was examined in adult male Wistar rats, in the elevated plus maze, spontaneous locomotor activity, and grip strength tests, mainly predictive of anxiolytic, sedative and myorelaxant actions, respectively. All investigated Stachys extracts lacked anxiolytic or myorelaxant activities, while SB at 400 mg/kg exerted an anxiogenic-like effect. The study with the selective antagonist beta-CCt showed that the sedative effect of SAD was only partially mediated by GABAA receptors containing the alpha1-subunit. While discernible, the behavioral effects of SA and SP were not distinct. In all extracts, chlorogenic acid and verbascoside were identified. In SA, SB, and SAD the flavonoid fraction was constituted of isoscutellarein and hypolaetine glycosides, while in SP chrysoeriol and apigenin glycosides were present. The results reveal the psychotropic potential of four endemic Stachys taxa, of which SAD appeared most promising as a natural sedative.

Novel positive allosteric modulators of GABAA receptors: do subtle differences in activity at alpha1 plus alpha5 versus alpha2 plus alpha3 subunits account for dissimilarities in behavioral effects in rats?

Over the last years, genetic studies have greatly improved our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABA(A) receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABA(A) receptors containing the alpha(1) subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently synthesized BZ site ligands: SH-053-2'N, SH-053-S-CH3-2'F, SH-053-R-CH3-2'F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of, respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABA(A) receptors containing the alpha(1) subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably alpha(1) receptor-mediated sedative effects of GABA(A) modulation were not fully eliminated with any of the ligands tested, only SH-053-2'N and SH-053-S-CH3-2'F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at alpha(2)- and alpha(3)-GABA(A) receptors, may have been partly connected with its preferential affinity at alpha(5)-GABA(A) receptors coupled with weak agonist activity at alpha(1)-containing subtypes. The memory impairment in water-maze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at alpha(1) GABA(A) receptors is needed for affecting spatial learning and memory impairments, while much weaker activity at alpha(1)- and alpha(5)-GABA(A) receptors is sufficient for eliciting sedation.

The differential role of alpha1- and alpha5-containing GABA(A) receptors in mediating diazepam effects on spontaneous locomotor activity and water-maze learning and memory in rats.

The clinical use of benzodiazepines (BZs) is hampered by sedation and cognitive deterioration. Although genetic and pharmacological studies suggest that alpha1- and alpha5-containing GABA(A) receptors mediate and/or modulate these effects, their molecular substrate is not fully elucidated. By the use of two selective ligands: the alpha1-subunit affinity-selective antagonist beta-CCt, and the alpha5-subunit affinity- and efficacy-selective antagonist XLi093, we examined the mechanisms of behavioural effects of diazepam in the tests of spontaneous locomotor activity and water-maze acquisition and recall, the two paradigms indicative of sedative- and cognition-impairing effects of BZs, respectively. The locomotor-activity decreasing propensity of diazepam (significant at 1.5 and 5 mg/kg) was antagonized by beta-CCt (5 and 15 mg/kg), while it tended to be potentiated by XLi093 in doses of 10 mg/kg, and especially 20 mg/kg. Diazepam decreased acquisition and recall in the water maze, with a minimum effective dose of 1.5 mg/kg. Both antagonists reversed the thigmotaxis induced by 2 mg/kg diazepam throughout the test, suggesting that both GABA(A) receptor subtypes participate in BZ effects on the procedural component of the task. Diazepam-induced impairment in the declarative component of the task, as assessed by path efficiency, the latency and distance before finding the platform across acquisition trials, and also by the spatial parameters in the probe trial, was partially prevented by both, 15 mg/kg beta-CCt and 10 mg/kg XLi093. Combining a BZ with beta-CCt results in the near to control level of performance of a cognitive task, without sedation, and may be worth testing on human subjects.