Histological reappraisal of IgA nephropathy: the role of glomerular pattern of injury and mesangial complement deposition.

BACKGROUND: There is a clear need to refine the histological assessment in IgA Nephropathy (IgAN). We sought to investigate the clinical significance of the light microscopy (LM) pattern of glomerular injury and of the intensity of mesangial C3 staining in IgAN. METHODS: We conducted a retrospective, observational study that included all patients with biopsy-proven primary IgAN that had at least 12 months of follow-up. The LM pattern of glomerular injury was reevaluated based on a modified HAAS classification. Mesangial C3 deposition by immunofluorescence (IF) staining was scored semi-quantitatively. The study primary composite endpoint was defined as doubling of serum creatinine or ESRD (dialysis, renal transplant or eGFR < 15 ml/min). The secondary study endpoint was eGFR decline per year. RESULTS: This cohort included 214 patients with IgAN (mean age, 41.4 ± 12.6 years), with a mean eGFR and median 24-h proteinuria of 55.2 ± 31.5 ml/min/1.73m2 and 1.5 g/day (IQR:0.8-3.25), respectively. The most frequent LM pattern was the mesangioproliferative (37.4%), followed by the sclerotic (22.5%) and proliferative/necrotizing patterns (21.4%). Regarding the IF findings, mild-moderate and intense mesangial C3 staining was present in 30.6% and 61.1% of patients, respectively. Those with sclerosing and crescentic patterns had the worst renal survival (5-year renal survival of 48.8% and 42.9%) and the highest rate of eGFR change/year (-2.32 ml/min/y and - 2.16 ml/min/y, respectively) compared to those with other glomerular patterns of injury. In addition, those with intense C3 staining reached the composite endpoint more frequently compared to those without intense C3 staining (35.5% vs. 21.4%, p = 0.04). After multivariate adjustment, patients with crescentic and sclerosing patterns had a 3.6-fold and 2.1-fold higher risk for the composite endpoint compared to those with mesangioproliferative pattern, while an intense mesangial C3 deposition being also associated with a worse renal outcome (HR, 3.33; 95%CI, 1.21-9.2). CONCLUSIONS: We have shown that the LM pattern of glomerular injury and the intensity of mesangial C3 deposition might stratify more accurately the renal outcome in patients with IgAN.

Enoxaparin versus Unfractionated Heparin for the Perioperative Anticoagulant Therapy in Patients with Mechanical Prosthetic Heart Valve Undergoing Non-Cardiac Surgery.

Background and Objectives: Immediate postoperative anticoagulation regimens in patients with mechanical prosthetic valves undergoing non-cardiac surgery are clear only for unfractionated heparin (UH), whereas the few low-molecular-weight heparin (LMWH) trials available to date concern the use of Enoxaparin in general/orthopedic surgery. We performed a single-center real-world data study comparing the efficacy and safety of LMWH­Enoxaparin (E)­ and UH during the perioperative period in non-cardiac surgical procedures in patients with mechanical prosthetic valve replacement in the mitral, aortic, or tricuspid positions. Materials and Methods: We enrolled 380 patients, who received E or UH together with oral anticoagulation with antivitamin K (acenocoumarol) until they achieved an optimal International Normalized Ratio (INR). Objective assessment of E efficacy included the following: normal value for all the parameters of ultrasound prosthetic functioning, no early thrombosis of the prosthesis, and rapid achievement of target INR with a decreased period of subcutaneous anticoagulation. Subjective assessment included the following: clinical improvement with decreased immobilization and in-hospital stay, fewer gluteal ulcerations, and fewer postoperative depression and anxiety episodes. Results: Comparing with UH, anticoagulation with E was more effective (p < 0.0001 and p = 0.02). The probability of death was smaller in the E group compared with the UH group. No major hemorrhagic event was reported. Mild bleeding episodes and thrombocytopenia were more common in the UH group. Patient's compliance and quality of life were better with E due to shortened hospitalization, decreased need for testing of coagulation (every 6 h for UH), better dosing (SC every 12 h for E versus continuous infusion for UH), shortened immobilization during the immediate postoperative period with subsequent improvement in the psychological status, as well as due to lack of significant side effects. Conclusions: Taking into consideration the improved efficiency and safety, as well as all the supplementary advantages, such as no need for anticoagulation monitoring, the ease of administration, and reduced duration of hospitalization, E should be seen as an attractive alternative for anticoagulation which deserves further investigation.

Impact of Pulmonary Hypertension on Mortality after Surgery for Aortic Stenosis.

Background and Objectives: The prognosis of patients with aortic stenosis (AS) adding pulmonary hypertension (PHT) is worse than in those with normal pulmonary artery pressure (PAP), and there are few results reported for the association between PHT and adverse outcomes of AS. We aimed to determine the predictive factors for the development of PHT in patients with surgical AS and to identify those factors that may predict the surgical prognosis. We aimed to identify the independent predictors for PHT regression at 2 years after surgery. Additionally, we tried to evaluate the involvement of PHT as an additional perioperative risk factor in patients with AS undergoing surgical aortic valve replacement (AVR). Materials and Methods: We carried out a two-year prospective study on 340 patients with AS undergoing surgical AVR. Results: The independent predictors for the occurrence of PHT in patients with surgical AS were: age > 75 years (RR = 6, p = 0.001), a restrictive left ventricle diastolic filling pattern (LVDFP) (RR = 9, p = 0.001) and associated moderate mitral regurgitation (MR) (RR = 9, p = 0.0001). The presence of severe PHT increased by 7.6 times the early postoperative risk of death, regardless of the presence of other parameters. The independent predictors for early postoperative mortality were: severe PHT, restrictive left ventricle diastolic pattern, age > 75 years, interventricular septum (IVS) thickness >18 mm and the presence of comorbidities. Conclusions: The presence of a severe PHT in patients with AS undergoing surgical AVR is associated with an early postoperative increased mortality rate. The mean PAP is a more reliable parameter for prognosis appreciation than the LV systolic function.

Additional Prognostic Value of Tissue Doppler Evaluation in Patients with Aortic Stenosis and Left-Ventricular Systolic Dysfunction Undergoing Aortic Valve Replacement.

Background and Objectives: Patients with surgical aortic stenosis (AS) show impaired diastolic filling, which is a risk factor for early and late mortality after aortic valve replacement (AVR). There is a paucity of information concerning the impact of restrictive diastolic filling and the evolution of diastolic dysfunction in the early and medium terms post-AVR. We aimed to determine the prognostic value of the presence of a restrictive left-ventricular (LV) diastolic filling pattern (LVDFP) and dilated left atrium (LA) in patients with AS and LV systolic dysfunction (LVEF < 40%) who underwent AVR, and to define the independent predictors for immediate and long-term prognosis and their value for preoperative risk estimation. Materials and Methods: The study was prospective and included 197 patients with surgical AS and LVEF <40% who underwent AVR. Preoperative echocardiographic examinations were repeated at day 10, at 1, 3 and 6 months, and at 1 and 2 years after surgery, with evaluation of LVEF, diastolic function and LA dimension index (mm/m2). Depending on LV systolic performance, patients were classified as Group A (LVEF: 30−40%) or Group B (LVEF < 30%). Results: The main echographic independent parameters for early and late postoperative death were: restrictive LVDFP, significant pulmonary hypertension, LV end-systolic diameter (LVESD) >55 mm and the presence of second-degree mitral regurgitation. Restrictive LVDFP and LA dimension >30 mm/m2 were independent predictors for fatal outcome (p = 0.0017). Conclusions: Assessment of diastolic function and LA dimension are reliable parameters in predicting fatal outcome and hospitalization for heart failure, having an independent and incremental prognostic value in patients with surgical AS. Complete evaluation of LVDFP with all the echographic measurements (including TDI) should routinely be part of the preoperative assessment of patients with LV systolic dysfunction undergoing AVR.

Diastolic versus Systolic Left Ventricular Dysfunction as Independent Predictors for Unfavorable Postoperative Evolution in Patients with Aortic Regurgitation Undergoing Aortic Valve Replacement.

Background and Objectives: Chronic severe aortic valve disease is associated with important changes in left ventricle (LV) performance associated with eccentric or concentric LV hypertrophy. We aimed to assess the immediate prognostic implications of the type of the LV diastolic filling pattern (LVDFP) compared with LV systolic performance in patients with severe aortic regurgitation (AR) undergoing aortic valve replacement (AVR) and to define the independent echographic predictors for the immediate and long-term prognoses. Materials and Methods: We performed a prospective study enrolling 332 AR patients undergoing AVR, divided into two groups: Group A­201 pts with normal LV systolic function, divided into two subgroups (A1: 129 pts with a nonrestrictive LVDFP and A2: 72 pts with restrictive LVDFP), and Group B­131 pts with LV systolic dysfunction (LV ejection fraction LVEF < 50%), divided into two subgroups (B1: 83 pts with a nonrestrictive LVDFP and B2: 48 pts with restrictive LVDFP). Results: The early postoperative mortality rate was higher in patients with a restrictive LVDFP (11.12% in A2 and 12.5% in B2) compared with normal LV filling (2.32% in A1 and 7.63% in B1, p < 0.0001), regardless of the LVEF. The restrictive LVDFP­defined by at least one of the following echographic parameters: an E/A > 2 with an E wave deceleration time (EDt) < 100 ms; an isovolumetric relaxation time (IVRT) < 60 ms; or an S/D ratio < 1 in the pulmonary vein flow­was an independent predictor for early postoperative mortality, increasing the relative risk by 8.2-fold. Other independent factors associated with early poor prognosis were an LV end-systolic diameter (LVESD) > 58 mm, an age > 75 years, and the presence of comorbidities (chronic obstructive pulmonary disease-COPD or diabetes mellitus). On a medium-term, an unfavorable evolution was associated with: an age > 75 years (RR = 8.1), an LV end-systolic volume (LVESV) > 95 cm3 (RR = 6.7), a restrictive LVDFP (RR = 9.8, p < 0.0002), and pulmonary hypertension (RR = 8.2). Conclusions: The presence of a restrictive LVDFP in patients with AR undergoing AVR is associated with both increased early and medium-term mortality rates. The LV diastolic function is a more reliable parameter for prognosis than LV systolic performance (RR 9.2 versus 2.1). Other independent predictors for increased early postoperative mortality rate were: an age > 75 years, an LVESD > 58 mm, and comorbidities (diabetes mellitus, COPD), and for unfavorable evolution at 2 years postoperatively: an age > 75 years, an LVESV > 95 cm3, and severe pulmonary hypertension.

Successful Treatment of Catastrophic Antiphospholipid Syndrome Using Rituximab: Case Report and Review of the Literature.

BACKGROUND: Kidney involvement is a frequent complication of systemic lupus erythematosus (SLE) and kidney biopsy is essential in differentiating lupus nephritis (LN) from thrombotic microangiopathy (TMA) secondary to antiphospholipid autoantibodies (aPL). Association between antiphospholipid syndrome (APS) and acquired hemophilia due to inhibitors was very rarely described in SLE patients. CASE PRESENTATION: We present the case of a 61-year-old male diagnosed with SLE who acquired deficiency of clotting factor VIII due to circulating inhibitors, admitted for acute kidney injury (AKI), microangiopathic hemolytic anemia, thrombocytopenia, and diplopia. Kidney biopsy showed TMA due to APS, but no signs of LN. Head computed tomography identified low dense areas in the white matter, suggesting small blood vessels' involvement. A diagnosis of probable catastrophic antiphospholipid syndrome (CAPS) was established and treatment with low molecular weight heparin, intravenous methylprednisolone, plasmapheresis, and rituximab was initiated, followed by resolution of AKI, diplopia, and TMA with complete depletion of CD19+B-lymphocytes (CD19+B-Ly) after one month. We further review the current knowledge regarding pathogenesis and management of CAPS in SLE patients. CONCLUSIONS: Targeted therapy was possible after kidney biopsy, improving renal and general prognosis. CD19+B-Ly repopulation preceded biological relapse, so monitoring of CD19+B-Ly may serve as a tool to predict relapses and guide rituximab therapy.

Clinical Predictors of Preeclampsia in Pregnant Women with Chronic Kidney Disease.

Background and Objectives: Pregnant women with chronic kidney disease (CKD) are at high risk of adverse maternal and fetal outcomes. Preeclampsia (PE) superimposed on CKD is estimated to occur in 21%-79% of pregnancies. Both conditions share common features such as proteinuria and hypertension, making differential diagnosis difficult. Objective: The aim of this study was to evaluate the incidence and the clinical-biological predictors of preeclampsia in pregnant women with CKD. Material and Methods: We retrospectively analyzed 34 pregnant women with pre-existing CKD admitted to our department between 2008 and 2017. Results: Among the 34 patients, 19 (55.8%) developed PE and the mean time of occurrence was 31.26 ± 2.68 weeks of gestation. The median value of 24-h proteinuria at referral was 0.87 g/day (interquartile range 0.42-1.50) and 47.1% of patients had proteinuria of ≥1 g/day. Patients with PE tended to be more hypertensive, with a more decreased renal function at referral and had significantly higher proteinuria (1.30 vs 0.63 g/day, p = 0.02). Cox multivariate analysis revealed that proteinuria ≥1 g/day at referral and pre-existing hypertension were independently associated with PE (adjusted hazard ratio = 4.10, 95% confidence interval: 1.52-11.02, p = 0.005, adjusted hazard ratio = 2.62, 95% confidence interval: 1.01-6.77, p = 0.04, respectively). The cumulative risk of PE was significantly higher in pregnant women with proteinuria ≥1 g/day at referral (log-rank, p = 0.003). Proteinuria ≥ 1 g/day at referral and pre-exiting hypertension predicted PE development with accuracies of 73.5% and 64.7%, respectively. Conclusions: Pregnant patients with pre-existing CKD are at high risk of developing preeclampsia, while proteinuria ≥ 1 g/day at referral and pre-existing hypertension were independent predictors of superimposed preeclampsia.

Inherited Risk Factors of Thromboembolic Events in Patients with Primary Nephrotic Syndrome.

Background and objectives. Venous thromboembolic events (VTEs) are among the most important complications of nephrotic syndrome (NS). We conducted a study that aimed to determine the prevalence of inherited risk factors for VTE in NS and to identify which factors are independent predictors of VTE. Materials and Methods. Thirty-six consecutive patients with primary NS that underwent percutaneous kidney biopsy between January 2017 and December 2017 were enrolled in this retrospective, observational study. VTEs were the primary outcome. Baseline demographic and biochemical data were collected from medical records, and genetic testing was done for polymorphisms of Factor V, PAI, MTHFR, and prothrombin genes. Results. The incidence of VTE was 28%, and the median time to event was 3 months (IQR: 2-9). The prevalence of inherited risk factors was 14% for Factor V Leiden mutation, 5.6% for prothrombin G20210A, 44.5% for PAI, and 27.8% for each of the two polymorphisms of the MTHFR gene. On multivariate analysis, the presence of at least two mutations was independently associated with the risk of VTE (HR, 8.92; 95% confidence interval, CI: 1.001 to 79.58, p = 0,05). Conclusions. These findings suggest that genetic testing for inherited thrombophilia in NS could play an important role in detecting high-risk patients that warrant prophylactic anticoagulation.

A single-arm pilot study of metformin in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Metformin has shown promising results regarding cystogenesis inhibition in preclinical studies with autosomal dominant polycystic kidney disease (ADPKD) models. We designed a prospective, preliminary, single-arm study to evaluate the tolerability, safety and the effect of Metformin on kidney function and body mass index (BMI) in Romanian patients with ADPKD. METHODS: We enrolled 34 adult patients with ADPKD, chronic kidney disease (CKD) stages 1-5 not on dialysis and without diabetes mellitus. The primary endpoint was to assess the tolerability and safety of Metformin. The secondary endpoints evaluated changes in estimated glomerular filtration rate (eGFR), body mass index (BMI) and renal replacement therapy (RRT) necessity. Patients received an initial dose of Metformin of 500 mg/day within the first month that was increased to 1000 mg/day thereafter according to tolerability. Change in eGFR and BMI was expressed as mean difference with the corresponding 95% confidence intervals and as a percentage. For the primary endpoint, we included all 34 enrolled patients. To assess the secondary endpoint, intention-to-treat (ITT) and per-protocol (PP) analysis was performed. RESULTS: Sixteen patients out of 34 completed the follow-up period at 24 months. Eighteen patients developed adverse events and 63.6% of these events were gastrointestinal related. Nausea was the most common adverse event (17.6%). Two patients (5.8%) permanently discontinued medication due to adverse events. We recorded no case of hypoglycemia, lactic acidosis or death. Mean eGFR changed by - 1.57 ml/min/1.73m2 (95%CI:-22.28 to 19.14, P = 0.87) in ITT and by - 4.57 ml/min/1.73m2 (95%CI:-28.03 to 18.89, P = 0.69) in PP population. Mean BMI change was - 1.10 kg/m2 (95%CI:-3.22 to 1.02, P = 0.30) in ITT population and - 0.80 kg/m2 (95%CI:-3.27 to 1.67, P = 0.51) in PP analysis. Three patients (8.8%) needed RRT. CONCLUSIONS: Metformin was well tolerated, had a good safety profile even in ADPKD patients with advanced CKD and it was not associated with change in eGFR or BMI across the follow-up period. TRIAL REGISTRATION: The study was retrospectively registered on https://www.isrctn.com (number ISRCTN 93749377); date registered: 02/25/2019.

Validation study of Oxford Classification of IgA Nephropathy: the significance of extracapillary hypercellularity and mesangial IgG immunostaining.

The Oxford classification (OC) of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as predictors of outcome. We aimed to validate the OC and to investigate the clinical significance of extracapillary hypercellularity and IgG immunostaining. We examined the renal outcome at December 31, 2014, of 121 adult patients with biopsy proven primary IgAN between 2003 and 2013. The primary endpoint was doubling of serum creatinine or renal replacement therapy initiation. The mean observation period was 59.7 months. Thirty-one percent of the patients presented with a grade of extracapillary hypercellularity. In comparison with the group with no crescents, they had higher grade of inflammation, lower eGFR and increased proteinuria. There were no differences between the IgA and IgA&IgG immunostaining groups regarding the disease progression risk factors. Mean kidney survival time for the entire cohort was 10.6 (9.1, 12.0) years. In the Cox regression model, the independent predictors of decreased renal survival were eGFR at time of biopsy, S1 and the presence of crescents. Our study showed that extracapillary proliferation and S1 had the greatest importance in establishing the renal prognosis of patients with IgAN.

Sodium citrate versus sodium bicarbonate for metabolic acidosis in patients with chronic kidney disease: A randomized controlled trial.

BACKGROUND: Metabolic acidosis (MA) is frequently associated with chronic kidney disease (CKD) progression. Our aim was to compare the effect of oral sodium citrate (SC) with that of oral sodium bicarbonate (SB) on renal function and serum bicarbonate correction, as well as to evaluate their safety profile in patients with MA of CKD. METHODS: We conducted a prospective, single-center, randomized 1:1, parallel, controlled, unblinded clinical trial of 124 patients with MA and CKD stages 3b and 4. The primary outcome was the mean change in estimated glomerular filtration rate (eGFR). The secondary outcomes were mean change in serum bicarbonate level, eGFR decrease by 30%, eGFR decrease by 50%, dialysis, death or prolonged hospitalization, and a combined endpoint. RESULTS: No significant difference was found between the groups in terms of mean eGFR change [adjusted mean difference = -0.99 mL/min/1.73 m2 (95% CI: -2.51 to 0.93, P = .20)]. We observed a mean serum bicarbonate change of 6.15 mmol/L [(95% CI: 5.55-6.74), P < .001] in the SC group and of 6.19 mmol/L [(95% CI: 5.54-6.83), P < .001] in the SB group, but no significant difference between the 2 groups [adjusted mean difference = 0.31 mmol/L (-0.22 to 0.85), P = .25]. Cox proportional hazard analysis showed similar risks regarding eGFR decrease by 30% (P = .77), eGFR decrease by 50% (P = .50), dialysis (P = .85), death or prolonged hospitalization (P = .29), and combined endpoint (P = .57). Study drug discontinuation due to adverse events was significantly more common in the SB group (17.7% vs 4.8%, P = .02). CONCLUSIONS: SC and SB have a similar effect on kidney function decline, both improve serum bicarbonate level, but SB is associated with higher rates of medication discontinuation due to adverse events.

Genotype-Phenotype Correlations in Alport Syndrome-A Single-Center Experience.

BACKGROUND: Alport syndrome (AS) is a common and heterogeneous genetic kidney disease, that often leads to end-stage kidney disease (ESKD). METHODS: This is a single-center, retrospective study that included 36 adults with type IV collagen (COL4) mutations. Our main scope was to describe how genetic features influence renal survival. RESULTS: A total of 24 different mutations were identified, of which eight had not been previously described. Mutations affecting each of the type IV collagen α chains were equally prevalent (33.3%). Most of the patients had pathogenic variants (61.1%). Most patients had a family history of kidney disease (71%). The most prevalent clinical picture was nephritic syndrome (64%). One-third of the subjects had extrarenal manifestations, 41.6% of patients had ESKD at referral, and another 8.3% developed ESKD during follow-up. The median renal survival was 42 years (95% CI, 29.98-54.01). The COL4A4 group displayed better renal survival than the COL4A3 group (p = 0.027). Patients with missense variants had higher renal survival (p = 0.023). Hearing loss was associated with lower renal survival (p < 0.001). CONCLUSIONS: Patients with COL4A4 variants and those with missense mutations had significantly better renal survival, whereas those with COL4A3 variants and those with hearing loss had worse prognoses.

Challenges Regarding the Value of Routine Perioperative Transesophageal Echocardiography in Mitral Valve Surgery.

BACKGROUND AND OBJECTIVES: Transesophageal echocardiography (TEE) is considered an indispensable tool for perioperative evaluation in mitral valve (MV) surgery. TEE is routinely performed by anesthesiologists competent in TEE; however, in certain situations, the expertise of a senior cardiologist specializing in TEE is required, which incurs additional costs. The purpose of this study is to determine the indications for specialized perioperative TEE based on its utility and the correlation between intraoperative TEE diagnoses and surgical findings, compared with routine TEE performed by an anesthesiologist. MATERIALS AND METHODS: We conducted a three-year prospective study involving 499 patients with MV disease undergoing cardiac surgery. Patients underwent intraoperative and early postoperative TEE and at least one other perioperative echocardiographic evaluation. A computer application was dedicated to calculating the utility of each type of specialized TEE indication depending on the type of MV disease and surgical intervention. RESULTS: The indications for performing specialized perioperative TEE identified in our study can be categorized into three groups: standard, relative, and uncertain. Standard indications for specialized intraoperative TEE included establishing the mechanism and severity of MR (mitral regurgitation), guiding MV valvuloplasty, diagnosing associated valvular lesions post MVR (mitral valve replacement), routine evaluations in triple-valve replacements, and identifying the causes of acute, intraoperative, life-threatening hemodynamic dysfunction. Early postoperative specialized TEE in the intensive care unit (ICU) is indicated for the suspicion of pericardial or pleural effusions, establishing the etiology of acute hemodynamic dysfunction, and assessing the severity of residual MR post valvuloplasty. CONCLUSIONS: Perioperative TEE in MV surgery can generally be performed by a trained anesthesiologist for standard measurements and evaluations. In certain cases, however, a specialized TEE examination by a trained senior cardiologist is necessary, as it is indirectly associated with a decrease in postoperative complications and early postoperative mortality rates, as well as an improvement in immediate and long-term prognoses. Also, for standard indications, the correlation between surgical and TEE diagnoses was superior when specialized TEE was used.

Neurological and Dermatological Manifestations of Tuberous Sclerosis Complex: Report from a Romanian Tertiary Hospital Cohort.

Tuberous sclerosis complex is a rare multisystem genetic disorder characterized by multiorgan involvement, frequently associated with intellectual impairment and epilepsy. The aim of our study was to describe the neurological and dermatological manifestations of TSC in 32 adult patients (of whom 19 were females) who attended the Neurology and Nephrology Clinics of Fundeni Clinical Institute in Romania from 2015 to 2020. Seventeen patients were diagnosed with epilepsy, nine patients had intellectual impairment, and complete neuroimaging was available for twenty-two patients. As expected, the most frequent dermatological lesions were cutaneous angiofibromas in 20 patients, but with a lower frequency than described in the current literature. Statistical analysis was performed considering the small number of patients. Cortical tubers in neuroimaging seemed to be associated with the diagnosis of epilepsy, while subependymal nodules represented a risk factor for intellectual impairment. Males showed a larger number of dermatological types of lesions, especially café -au-lait patches. Interestingly, we found a statistically significant positive association between epilepsy and the presence of cutaneous angiofibromas, as well as total dermatological involvement. Females had significantly higher Charlson comorbidity index scores, indicating a higher burden of disease. Everolimus seemed to be a well-tolerated treatment and showed promising results in controlling epileptic seizures alone in two patients. More studies, with the inclusion of a larger number of patients, are needed to confirm these results.

Incidence and Risk Factors for Long-Term Persistence of Diastolic Dysfunction after Aortic Valve Replacement for Aortic Stenosis Compared with Aortic Regurgitation.

(1) Background: Severe left ventricular (LV) diastolic dysfunction with a restrictive diastolic pattern (LVDFP) is generally associated with a worse prognosis. Its evolution and reversibility in the short- and medium-term after aortic valve replacement (AVR) has been little-studied. We aimed to evaluate the evolution of LV remodeling and LV systolic and diastolic function after AVR in aortic stenosis (AS) patients compared to aortic regurgitation (AR). Moreover, we tried to identify the main predictive parameters for postoperative evolution (cardiovascular hospitalization or death and quality of life) and the independent predictors for the persistence of restrictive LVDFP after AVR. (2) Methods: A five-year prospective study on 397 patients undergoing AVR for AS (226 pts) or AR (171 pts), evaluated clinically and by echocardiography preoperatively and until 5 years postoperatively. (3) Results: 1. In patients with AS, early post AVR, LV dimensions decreased and diastolic filling and LV ejection fraction (LVEF) improved more rapidly compared to patients with AR. At 1 year postoperatively, persistent restrictive LVDFP was found especially in the AR group compared to the AS group (36.84% vs. 14.16%). 2. Cardiovascular event-free survival at the 5-year follow-up was lower in the AR group (64.91% vs. 87.17% in the AS group). The main independent predictors of short- and medium-term prognosis after AVR were: restrictive LVDFP, severe LV systolic dysfunction, severe pulmonary hypertension (PHT), advanced age, severe AR, and comorbidities. 3. The persistence of restrictive LVDFP after AVR was independently predicted by: preoperative AR, the E/Ea ratio > 12, the LA dimension index > 30 mm/m2, an LV endsystolic diameter (LVESD) > 55 mm, severe PHT, and associated second-degree MR (p < 0.05). (4) Conclusions: AS patients had an immediate postoperative evolution in terms of LV remodeling, and LV systolic and diastolic function were more favorable compared to those with AR. The restrictive LVDFP was reversible, especially after the AVR for AS. The main prognostic predictors were the presence of restrictive LVDFP, advanced age, preoperative AR, severe LV systolic dysfunction, and severe PHT.

Hantavirus infections in the South­Eastern European countries: A study of two cases and literature review.

Hantavirus infection is a rare zoonosis in South-Eastern Europe. Depending on the serotype involved, the virus can cause hemorrhagic fever with renal syndrome which is also known as endemic nephropathy, and cardiopulmonary syndrome. Prompt diagnosis of the disease is essential for reducing the risk of severe manifestations and complications like chronic kidney disease, secondary hypertension or even death because there is no specific treatment or vaccine approved. The present study reported two cases of hemorrhagic fever with renal syndrome diagnosed in the Department of Nephrology of The Fundeni Clinical Institute (Romania). In both patients, kidney needle biopsy played a major role in establishing the diagnosis. The difficulties encountered in diagnosing this disease were also emphasized, taking into consideration the rarity of this infection in South-Eastern Europe. The key literature data on the epidemiology, pathogenesis and management of this infection were further reviewed.

An open-label study evaluating the safety and efficacy of budesonide in patients with IgA nephropathy at high risk of progression.

We sought to evaluate the efficacy and safety of budesonide (Budenofalk) in the treatment of patients with IgA Nephropathy. We conducted a prospective, interventional, open-label, single-arm, non-randomized study that enrolled 32 patients with IgAN at high risk of progression (BUDIGAN study, ISRCTN47722295, date of registration 14/02/2020). Patients were treated with Budesonide at a dose of 9 mg/day for 12 months, subsequently tapered to 3 mg/day for another 12 months. The primary endpoints were change of eGFR and proteinuria at 12, 24 and 36 months. The study cohort had a mean eGFR and 24-h proteinuria of 59 ± 24 ml/min/1.73m2 and 1.89 ± 1.5 g/day, respectively. Treatment with budesonide determined a reduction in proteinuria at 12-, 24- and 36-months by -32.9% (95% CI - 53.6 to - 12.2), - 49.7% (95% CI - 70.1 to - 29.4) and - 68.1% (95% CI - 80.6 to - 55.7). Budesonide determined an eGFR preservation corresponding to a 12-, 24- and 36-months change of + 7.68% (95% CI - 4.7 to 20.1), + 7.42% (95% CI - 7.23 to 22.1) and + 4.74% (95%CI - 13.5 to 23), respectively. The overall eGFR change/year was + 0.83 ml/min/y (95% CI - 0.54 to 4.46). Budesonide was well-tolerated, and treatment emergent adverse events were mostly mild in severity and reversible. Budesonide was effective in the treatment of patients with IgAN at high-risk of progression in terms of reducing proteinuria and preserving renal function over 36 months of therapy.

Challenges in Caring for People with Cardiovascular Disease through and beyond the COVID-19 Pandemic: The Advantages of Universal Access to Home Telemonitoring.

(1) Background: Cardiovascular prevention was left in second place during the COVID-19 pandemic and the use of telemedicine turned out to be very useful. We aimed to evaluate the effectiveness of a telemedicine application for remote monitoring and treatment adjustments in terms of improving cardiovascular prevention. (2) Methods: A prospective study of 3439 patients evaluated between the 1st of March 2019 and the 1st of March 2022, in the pre-pandemic period by face-to-face visits and during the pandemic by teleconsultations or hybrid follow-up. We compared four periods: pre-pandemic-Pre-P (1 March 2019-1 March 2020), lockdown-Lock (1 March-1 September 2020), restrictive-pandemic-Restr-P (1 September 2020-1 March 2021), and relaxed-pandemic-Rel-P (1 March 2021-1 March 2022). (3) Results: The average values of total cholesterol (TC), LDL cholesterol, triglycerides, uric acid, and glucose had an increasing trend during Lock and Restr-P, and they decreased close to the baseline level during the Rel-P, with the exception of glucose which remained elevated in Rel-P. The number of patients with newly discovered DM increased significantly in the Rel-P, and 79.5% of them had mild/moderate forms of COVID-19. During Lock and Res-P, the percentage of obese, smoking, or hypertensive patients increased, but probably through the use of telemedicine, we managed to reduce it, although it remained slightly higher than the pre-pandemic level. Physical activity decreased in the first year of the pandemic, but in Rel-P people became more active than before the pandemic. (4) Conclusions: The use of telemedicine for cardiovascular prevention seems to yield favorable results, especially for secondary prevention in the very high-risk group and during the second year.

Oral Furosemide and Hydrochlorothiazide/Amiloride versus Intravenous Furosemide for the Treatment of Resistant Nephrotic Syndrome.

BACKGROUND: Data on diuretic treatment in nephrotic syndrome (NS) are scarce. Our goal was to assess the non-inferiority of the combined oral diuretics (furosemide/hydrochlorothiazide/amiloride) compared to intravenous (i.v.) furosemide in patients with NS and resistant edema. METHODS: We conducted a prospective randomized trial on 22 patients with resistant nephrotic edema (RNE), defined as hypervolemia and a FENa < 0.2%. Based on a computer-generated 1:1 randomization, we assigned patients to receive either intravenous furosemide (40 mg bolus and then continuous administration of 5 mg/h) or oral furosemide (40 mg/day) and hydrochlorothiazide/amiloride (50/5 mg/day) for a period of 5 days. Clinical and laboratory measurements were performed daily. Hydration status was assessed by bioimpedance on day 1 and at the end of day 5 after treatment initiation. The primary endpoint was weight change from baseline to day 5. Secondary endpoints were hydration status change measured by bioimpedance and safety outcomes (low blood pressure, severe electrolyte disturbances, acute kidney injury and worsening hypervolemia). RESULTS: Primary endpoint analysis showed that after 5 days of treatment, there was a significant difference in weight change from baseline between groups [adjusted mean difference: -3.33 kg (95% CI: -6.34 to -0.31), p = 0.03], with a higher mean weight change in the oral diuretic treatment group [-7.10 kg (95% CI: -18.30 to -4.30) vs. -4.55 kg (95%CI: -6.73 to -2.36)]. Secondary endpoint analysis showed that there was no significant difference between groups regarding hydration status change [adjusted mean difference: -0.05 L (95% CI: -2.6 to 2.6), p = 0.96], with a mean hydration status change in the oral diuretic treatment group of -4.71 L (95% CI: -6.87 to -2.54) and -3.91 L (95% CI: -5.69 to -2.13) in the i.v. diuretic treatment group. We observed a significant decrease in adjusted mean serum sodium of -2.15 mmol/L [(95% CI: -4.25 to -0.05), p = 0.04]), favored by the combined oral diuretic treatment [-2.70 mmol/L (95% CI: -4.89 to -0.50) vs. -0.10 mmol/L (95%CI: -1.30 to 1.10)]. No statistically significant difference was observed between the two groups in terms of adverse events. CONCLUSIONS: A combination of oral diuretics based on furosemide, amiloride and hydrochlorothiazide is non-inferior to i.v. furosemide in weight control of patients with RNE and a similar safety profile.

Importance of Tissue Doppler Evaluation in Dilated Cardiomyopathy: The Value of Diastolic Filling Pattern as a Prognostic Predictor.

(1) Background: The presence of restrictive left ventricular diastolic filling pattern (LVDFP) is associated with an unfavorable prognosis in many cardiac diseases, but few data are available on the prognostic implications of this pattern in patients with dilated cardiomyopathy (DCM). We aimed to establish the main prognostic predictors at the 1- and 5-year follow-ups in DCM patients and the value of restrictive LVDFP in increasing morbidity and mortality. (2) Methods: A prospective study of 143 patients with DCM divided in non-restrictive LVDFP group (95 patients) and restrictive group (47 patients). The patients were evaluated at a 5-year follow-up through an in-patient visit during the pre-pandemic period and hybrid methods (face-to-face, teleconsultation and home monitoring with a telemedicine application) during the pandemic period. Statistical analysis compared the two groups in terms of NYHA class, quality of life, hospitalizations/emergency department (ED) visits due to HF exacerbation and total mortality. (3) Results: The mortality rate in the restrictive group was markedly higher than that in the non-restrictive group at 1 year (17.02% vs. 10.59%, respectively, p < 0.05) and at 5 years (68.08% vs. 50.53%, p < 0.05). In the restrictive group, hospitalizations/ED visits due to HF decompensations at 1 year were significantly higher (85.11% vs. 57.89%, p < 0.05), with hospitalizations for ventricular arrhythmia being almost three times higher (21.28% vs. 7.37%, respectively, p < 0.05). The percentage of patients with a favorable evolution (in terms of NYHA class and quality of life) at the 1- and 5-year follow-ups were higher in the non-restrictive LVDFP group. The main prognostic predictors in patients with DCM at the 1-year follow-up were: restrictive LVDFP, age > 75 years, markedly dilated LV, comorbidities (DM, COPD), 2nd-degree mitral regurgitation and severe pulmonary hypertension (p < 0.05). (4) Conclusions: At the 1- and 5-year follow-ups, the presence of the restrictive LVDFP in DCM patients was independently associated with a poor prognosis, being the best clinical predictor for unfavorable evolution, after adjustment for other well-established predictive parameters in DCM patients.