Sodium-glucose cotransporter 2 inhibition in primary and secondary glomerulonephritis.

BACKGROUND: The role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the management glomerular/systemic autoimmune diseases with proteinuria in real-world clinical settings is unclear. METHODS: This is a retrospective, observational, international cohort study. Adult patients with biopsy-proven glomerular diseases were included. The main outcome was the percentage reduction in 24-h proteinuria from SGLT2i initiation to 3, 6, 9 and 12 months. Secondary outcomes included percentage change in estimated glomerular filtration rate (eGFR), proteinuria reduction by type of disease and reduction of proteinuria ≥30% from SGLT2i initiation. RESULTS: Four-hundred and ninety-three patients with a median age of 55 years and background therapy with renin-angiotensin system blockers were included. Proteinuria from baseline changed by -35%, -41%, -45% and -48% at 3, 6, 9 and 12 months after SGLT2i initiation, while eGFR changed by -6%, -3%, -8% and -10.5% at 3, 6, 9 and 12 months, respectively. Results were similar irrespective of the underlying disease. A correlation was found between body mass index (BMI) and percentage proteinuria reduction at last follow-up. By mixed-effects logistic regression model, serum albumin at SGLT2i initiation emerged as a predictor of ≥30% proteinuria reduction (odds ratio for albumin <3.5 g/dL, 0.53; 95% CI 0.30-0.91; P = .02). A slower eGFR decline was observed in patients achieving a ≥30% proteinuria reduction: -3.7 versus -5.3 mL/min/1.73 m2/year (P = .001). The overall tolerance to SGLT2i was good. CONCLUSIONS: The use of SGLT2i was associated with a significant reduction of proteinuria. This percentage change is greater in patients with higher BMI. Higher serum albumin at SGLT2i onset is associated with higher probability of achieving a ≥30% proteinuria reduction.

Glomerular Diseases Across Lifespan: Key Differences in Diagnostic and Therapeutic Approaches.

Glomerular diseases are common causes of chronic kidney disease in childhood, adolescence, and adulthood. The epidemiology of glomerular diseases differs between different age groups, with minimal change disease being the leading cause of nephrotic syndrome in childhood, while membranous nephropathy and focal segmental glomerulosclerosis are more common in adulthood. IgA vasculitis is also more common in childhood. Moreover, there is a difference in disease severity with more children presenting with a relapsing form of nephrotic syndrome and a more acute presentation of antineutrophil cytoplasmic antibody-associated vasculitis and concomitant glomerulonephritis, as highlighted by the higher percentage of cellular crescents on kidney biopsy specimens in comparison with older patients. There is also a female preponderance in antineutrophil cytoplasmic antibody-associated vasculitis and more children present with tracheobroncholaryngeal disease. This article aims to summarize differences in the presentation of different glomerular diseases that are encountered commonly by pediatric and adult nephrologists and potential differences in the management.

[Diagnosis and treatment of Minimal Change Disease in adults-2023]. / Diagnostik und Therapie der Minimal Change Glomerulopathie beim Erwachsenen ­ 2023.

Minimal change disease is a glomerulopathy that clinically manifests as acute onset nephrotic syndrome. A diagnosis is made by renal biopsy, implying the absence of glomerular lesions on light microscopy but detection of extensive podocyte foot process effacement on electron miscroscopy. Considering the typically excellent response to immunosuppressive measures (especially to glucocorticoids), an autoimmune pathogenesis is assumed. Although general prognosis is overall beneficial, steroid-dependent, steroid-resistant and frequently-relapsing disease courses may complicate the management of these patients and necessitate the use of alternative immunosuppressive treatment strategies. Here, the Austrian Society of Nephrology (ÖGN) provides a consensus on how to best diagnose and manage adult patients with minimal change disease.

[Diagnosis and treatment of glomerular diseases with a membranoproliferative glomerulonephritis (MPGN) pattern of injury]. / Diagnose und Therapie glomerulärer Erkrankungen mit einem membranoproliferativen Läsionsmuster (MPGN) ­ 2023.

Membranoproliferative glomerulonephritis (MPGN) represents a heterogeneous group of diseases. The common feature of a membranoproliferative lesion pattern in the kidney biopsy can either be idiopathic/primary or-much more frequently-have a secondary cause. The historical classification into MPGN types I to III has largely been abandoned and replaced in recent years by a pathogenesis-oriented classification. A MPGN with C1q, C3 and/or C4 deposits on light microscopy is referred to as immune complex GN (IC-GN), while a MPGN with dominant C3 deposits is referred to as C3 glomerulopathy (C3G). C3G is further divided into C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). These diagnoses can only be made by a kidney biopsy. Possible causes of MPGN are chronic infections (especially hepatitis B and C, bacterial infections, infections with protozoa), autoimmune diseases (especially lupus, rheumatoid arthritis) or malignancies (especially hematological malignancies). Particularly in the case of C3G a comprehensive analysis of the complement system components is strongly recommended. Due to the low incidence and the heterogeneous clinical appearance of MPGN therapeutic decisions must be made individually; an optimal general therapy is unknown, except that supportive treatment as with other glomerular diseases should be optimized. In the case of a secondary MPGN it is generally recommended to treat the potential cause of the MPGN. If significant proteinuria persists and eGFR remains > 30 ml/min/1.73 m2, treatment with systemic steroids and mycophenolate mofetil is recommended. Other treatment options on an individual level after evaluation and discussion of the risk-benefit ratio with the patient are rituximab and eculizumab. Rapidly progressive MPGN should be treated like ANCA-associated vasculitis. The recurrence rates after kidney transplantation are very high and treatment is challenging.

[Diagnosis and therapy of granulomatosis with polyangiitis and microscopic polyangiitis-2023: consensus of the Austrian society of nephrology (ÖGN) and Austrian society of rheumatology (ÖGR)]. / Diagnose und Therapie der Granulomatose mit Polyangiitis und mikroskopische Polyangiitis ­ 2023: Konsens-Empfehlungen der Österreichischen Gesellschaften für Nephrologie (ÖGN) & Rheumatologie (ÖGR).

ANCA-associated vasculitides (AAV) are rare, complex systemic diseases that are often difficult to diagnose, because of unspecific clinical symptoms at presentation. However, the clinical course may be very dramatic and even life-threatening, necessitating prompt diagnosis and treatment.Therefore, it is important to increase disease awareness among physicians and support colleagues who are not confronted with these rare diseases on a regular basis. Here, the Austrian Society of Nephrology (ÖGN) and the Austrian Society of Rheumatology (ÖGR) provide a joint consensus on how to best diagnose and manage patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

Critical Appraisal of Large Vitamin D Randomized Controlled Trials.

As a consequence of epidemiological studies showing significant associations of vitamin D deficiency with a variety of adverse extra-skeletal clinical outcomes including cardiovascular diseases, cancer, and mortality, large vitamin D randomized controlled trials (RCTs) have been designed and conducted over the last few years. The vast majority of these trials did not restrict their study populations to individuals with vitamin D deficiency, and some even allowed moderate vitamin D supplementation in the placebo groups. In these RCTs, there were no significant effects on the primary outcomes, including cancer, cardiovascular events, and mortality, but explorative outcome analyses and meta-analyses revealed indications for potential benefits such as reductions in cancer mortality or acute respiratory infections. Importantly, data from RCTs with relatively high doses of vitamin D supplementation did, by the vast majority, not show significant safety issues, except for trials in critically or severely ill patients or in those using very high intermittent vitamin D doses. The recent large vitamin D RCTs did not challenge the beneficial effects of vitamin D regarding rickets and osteomalacia, that therefore continue to provide the scientific basis for nutritional vitamin D guidelines and recommendations. There remains a great need to evaluate the effects of vitamin D treatment in populations with vitamin D deficiency or certain characteristics suggesting a high sensitivity to treatment. Outcomes and limitations of recently published large vitamin D RCTs must inform the design of future vitamin D or nutrition trials that should use more personalized approaches.

Rituximab as a Treatment Option after Autologous Hematopoietic Stem Cell Transplantation in a Patient with Systemic Sclerosis.

Systemic sclerosis (SSc) is an intractable autoimmune disease characterized by vasculopathy and organ fibrosis. Autologous hematopoietic stem cell transplantation (AHSCT) should be considered for the treatment of selected patients with rapid progressive SSc at high risk of organ failure. It, however, remains elusive whether immunosuppressive therapies such as rituximab (RTX) are still necessary for such patients after AHSCT, especially in those with bad outcomes. In the present report, a 43-year-old man with diffuse cutaneous SSc received AHSCT. Despite AHSCT, SSc further progressed with progressive symptomatic heart failure with newly developed concomitant mitral and tricuspid valve insufficiency, thus the patient started on RTX 8 months after AHSCT. Shortly after initiation of RTX, clinical symptoms and organ functions ameliorated subsequently. Heart valve regurgitations were reversible after initiation of RTX treatment. Currently, the patient remains in a stable condition with significant improvement of clinical symptoms and organ functions. Reporting about therapies after AHSCT in SSc is a very important issue, as randomized controlled trials are lacking, and therefore this report adds to evidence that RTX can be considered as a treatment option in patients with SSc that do not respond to AHSCT.

Effect of short-interval rituximab and high-dose corticosteroids on kidney function in systemic sclerosis: Long-term experience of a single centre.

INTRODUCTION: Scleroderma renal crisis (SRC) is a rare but one of the most recognised complications of systemic sclerosis (SSc). Corticosteroid (CS) use has been considered as a major risk factor for SRC. Several studies reported the efficacy of rituximab (RTX) with an acceptable safety profile in SSc. However, data on the long-term effect of high-dose CS concomitant to RTX on kidney function are lacking. METHODS: We retrospectively analysed SSc patients (n = 35) treated with a lower dosage and short-interval RTX and concomitant high-dose CS at the Department of Internal Medicine at the Medical University of Graz between 2010 and 2019. The kidney function was assessed using the estimated glomerular filtration rate (eGFR) at every RTX admission. The annual decline of kidney function was evaluated by linear mixed model analysis. RESULTS: At the RTX initiation, one patient had a decreased kidney function indicated by eGFR < 60 mL/min/1.73 m2 (median: 96 mL/min/1.73 m2 ; interquartile range (IQR): 43-136). Patients received RTX and complementary high-dose CS for a median follow-up time of 3.4 years (range 0.6-9.5). A linear mixed model analysis with the patient as random effect and time from first RTX as fixed effect estimated an annual decline of 1.98 mL/min/1.73 m2 of the eGFR (95% confidence interval: [-2.24, -1.72]; P <.001). During the follow-up period, no patient experienced SRC or a significant drop in kidney function. CONCLUSIONS: A regular, high-dose CS given contemporary to RTX seems to be a safe option for kidney function in patients with SSc. Our findings provide additional knowledge in risk evaluation and planning of individualised therapies or designing clinical studies using RTX.

Acute and Chronic Kidney Dysfunction and Outcome After Stroke Thrombectomy.

Data on the impact of kidney dysfunction on outcome in patients with stroke due to large vessel occlusion are scarce. The few available studies are limited by only considering single kidney parameters measured at one time point. We thus investigated the influence of both chronic kidney disease (CKD) and acute kidney injury (AKI) on outcome after mechanical thrombectomy. We included consecutive patients with anterior circulation large vessel occlusion stroke receiving mechanical thrombectomy at our center over an 8-year period. We extracted clinical data from a prospective registry and investigated kidney serum parameters at admission, the following day and throughout hospital stay. CKD and AKI were defined according to established nephrological criteria. Unfavorable outcome was defined as scores of 3-6 on the modified Rankin Scale 3 months post-stroke. Among 465 patients, 31.8% had an impaired estimated glomerular filtration rate (eGFR) at admission (< 60 ml/min/1.73 m2). Impaired admission eGFR was related to unfavorable outcome in univariable analysis (p = 0.003), but not after multivariable adjustment (p = 0.96). Patients frequently met AKI criteria at admission (24.5%), which was associated with unfavorable outcome in a multivariable model (OR 3.03, 95% CI 1.73-5.30, p < 0.001). Moreover, patients who developed AKI during hospital stay also had a worse outcome (p = 0.002 in multivariable analysis). While CKD was not associated with 3-month outcome, we identified AKI either at admission or throughout the hospital stay as an independent predictor of unfavorable prognosis in this study cohort. This finding warrants further investigation of kidney-brain crosstalk in the setting of acute stroke.

IL-1 receptor blockade skews inflammation towards Th2 in a mouse model of systemic sclerosis.

The interleukin (IL)-1 family of cytokines is strongly associated with systemic sclerosis (SSc) and pulmonary involvement, but the molecular mechanisms are poorly understood. The aim of this study was to assess the role of IL-1α and IL-1ß in pulmonary vascular and interstitial remodelling in a mouse model of SSc.IL-1α and IL-1ß were localised in lungs of SSc patients and in the fos-related antigen-2 (Fra-2) transgenic (TG) mouse model of SSc. Lung function, haemodynamic parameters and pulmonary inflammation were measured in Fra-2 TG mice with or without 8 weeks of treatment with the IL-1 receptor antagonist anakinra (25 mg·kg-1·day-1). Direct effects of IL-1 on pulmonary arterial smooth muscle cells (PASMCs) and parenchymal fibroblasts were investigated in vitroFra-2 TG mice exhibited increased collagen deposition in the lung, restrictive lung function and enhanced muscularisation of the vasculature with concomitant pulmonary hypertension reminiscent of the changes in SSc patients. Immunoreactivity of IL-1α and IL-1ß was increased in Fra-2 TG mice and in patients with SSc. IL-1 stimulation reduced collagen expression in PASMCs and parenchymal fibroblasts via distinct signalling pathways. Blocking IL-1 signalling in Fra-2 TG worsened pulmonary fibrosis and restriction, enhanced T-helper cell type 2 (Th2) inflammation, and increased the number of pro-fibrotic, alternatively activated macrophages.Our data suggest that blocking IL-1 signalling as currently investigated in several clinical studies might aggravate pulmonary fibrosis in specific patient subsets due to Th2 skewing of immune responses and formation of alternatively activated pro-fibrogenic macrophages.

Lung Function Changes are More Common in Marfan Patients Who Need Major Thoracic Surgery.

INTRODUCTION: Marfan syndrome is a genetic disorder affecting the connective tissue. Changes in lung tissue might influence respiratory function; however, a detailed respiratory functional assessment according to the need for major thoracic surgery is missing. METHODS: Comprehensive pulmonary examinations were performed in 55 Marfan patients including respiratory symptoms, lung function (LF) testing using European Coal and Steel Community (ECSC) reference values, TLCO and quality of life measurements. Groups included patients who did not need surgery (Mf, n = 32) and those who underwent major thoracic surgery (Mfop, n = 23). RESULTS: Respiratory symptoms affected 20% of patients. Scoliosis was significantly more frequent in the Mfop group. LF demonstrated in all Marfan patients a tendency towards airway obstruction (FEV1/FVC = 0.77 ± 0.10), more prominent in Mfop patients (0.74 ± 0.08 vs. Mf: 0.80 ± 0.11; p = 0.03). Correction of LF values using a standing height modification by arm span (Hcorrected) revealed additional changes in FVC and FEV1. TLCO and quality of life did not differ between groups. CONCLUSIONS: Marfan syndrome is associated with airway obstruction, especially in patients who have undergone major thoracic surgery, indicative of more severe connective tissue malfunction. The use of arm span for height correction is suitable to evaluate LF changes in this special patient group including patients with significant scoliosis.

Long time enzyme replacement therapy stabilizes obstructive lung disease and alters peripheral immune cell subsets in Fabry patients.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder, causing accumulation of globotriaosylceramid in different organs. Glycolipids are activators of different immune cell subsets the resulting inflammation is responsible for organ damage. Pulmonary involvement leads to airway inflammation; however, data on severity, as well as the effect of enzyme replacement therapy on lung function parameters and changes in peripheral immune cell subsets on lung involvement are sparse. METHODS: Seven Fabry patients and four carriers underwent detailed clinical examinations screening for pulmonary manifestations. Repetitive measurements were performed on five patients on ERT (average follow-up 5 years). Patients with Fabry disease and control volunteers were included into peripheral blood cell measurements. RESULTS: Lung involvement was present in all patients. Symptoms suggestive for lung disease were mild, however, obstructive ventilatory disorder, dominantly affecting small airways accompanied by hyperinflation was demonstrated in all affected patients. ERT resulted in small improvement of FEV1 in most treated patients. Decreased ratio of myeloid DC, Th17 cells while increase in T helper (Th)1 cells, and no change in Th2 and regulatory T (Treg) cells were detected in Fabry patients. CONCLUSIONS: Fabry disease results mainly in mild symptoms related to lung involvement, characterized by moderate non-reversible obstructive ventilatory disorder. Stabilization of airway obstruction during follow-up was observed using ERT in most patients, emphasizing the importance of this treatment in respect of pulmonary manifestations. Changes of immune cell subsets in the peripheral blood might play a role in inflammatory process, including small airways in Fabry patient's lung.

Bentall procedure: quarter century of clinical experiences of a single surgeon.

BACKGROUND: We retrospectively analyzed 25 years of experiences with the button Bentall procedure in patients with aortic root pathologies. Even though this procedure has become widespread, there are only a few very long term follow-ups available in the clinical literature, especially regarding single surgeon results. METHODS: Between 1988 and 2013, a total of 147 patients underwent the Bentall procedure by the same surgeon. Among them there were 62 patients with Marfan syndrome. At the time of the surgery the mean age was 46.5 ± 17.6 years. The impact of surgical experience on long-term survival was evaluated using a cumulative sum analysis chart. RESULTS: The Kaplan-Meier estimated overall survival rates for the 147 patients were 91.8 ± 2.3 %, 84.3 ± 3.1 %, 76.3 ± 4.9 % and 59.5 ± 10.7 % at 1,5,10 and 20 years, respectively. Multivariate Cox regression analysis identified EuroSCORE II over 3 % (OR 4.245, 95 % CI, 1.739-10.364, p = 0.002), acute indication (OR 2.942, 95 % CI, 1.158-7.480, p = 0.023), use of deep hypothermic circulatory arrest (OR 3.267, 95 % CI, 1.283-8.323, p = 0.013), chronic kidney disease (OR 6.865, 95 % CI, 1.339-35.189, p = 0.021) and early complication (OR 3.134, 95 % CI, 1.246-7.883, p = 0.015) as significant risk factors for the late overall death. The survival rate for freedom from early complication was 94.3 ± 2.2 %, 88.0 ± 3.3 %, 82.9 ± 4.7 % and 69.2 ± 8.4 % at 1,5,10 and 20 years. The main pathological findings of the aortic wall were cystic medial degeneration in 75 %, fibrosis in 6 %, atherosclerosis in 13 % and no pathological alteration in 6 % of the samples. The overall survival rate was significantly lower in patients operated in first 15 years compared to patients operated in the last decade (log-rank p = 0.011). CONCLUSION: According to our long-term follow-up the Bentall operation provides an appropriate functional result by resolving the lesions of the ascending aorta. Based on our results, 25-30 operations done is necessary to gain such a level of confidence and experience to aquire better results on long-term survival. In addition, we discussed that there were no co-morbidities affecting on the survival of Marfan patients and prophylactic aortic root replacement ensures a longer survival among patients with Marfan syndrome.

Possible extracardiac predictors of aortic dissection in Marfan syndrome.

BACKGROUND: According to previous studies, aortic diameter alone seems to be insufficient to predict the event of aortic dissection in Marfan syndrome (MFS). Determining the optimal schedule for preventive aortic root replacement (ARR) aortic growth rate is of importance, as well as family history, however, none of them appear to be decisive. Thus, the aim of this study was to search for potential predictors of aortic dissection in MFS. METHODS: A Marfan Biobank consisting of 79 MFS patients was established. Thirty-nine MFS patients who underwent ARR were assigned into three groups based on the indication for surgery (dissection, annuloaortic ectasia and prophylactic surgery). The prophylactic surgery group was excluded from the study. Transforming growth factor-ß (TGF-ß) serum levels were measured by ELISA, relative expression of c-Fos, matrix metalloproteinase 3 and 9 (MMP-3 and -9) were assessed by RT-PCR. Clinical parameters, including anthropometric variables - based on the original Ghent criteria were also analyzed. RESULTS: Among patients with aortic dissection, TGF-ß serum level was elevated (43.78 ± 6.51 vs. 31.64 ± 4.99 ng/l, p < 0.0001), MMP-3 was up-regulated (Ln2α = 1.87, p = 0.062) and striae atrophicae were more common (92% vs. 41% p = 0.027) compared to the annuloaortic ectasia group. CONCLUSIONS: We found three easily measurable parameters (striae atrophicae, TGF-ß serum level, MMP-3) that may help to predict the risk of aortic dissection in MFS. Based on these findings a new classification of MFS, that is benign or malignant is also proposed, which could be taken into consideration in determining the timing of prophylactic ARR.