Renin-Angiotensin-Aldosterone System: From History to Practice of a Secular Topic.

Renin-angiotensin-aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS and pose the question of whether this survival trait is still necessary to humankind in the present age. We elucidate the benefits on cardiovascular health and kidney disease of RAAS inhibition and present promising novel medications. Furthermore, we address why more studies are needed to establish a new standard of care away from generally prescribing ACEi or ARB toward an improved approach to combine drugs tailored to the needs of individual patients.

The Importance of Early Diagnosis and Intervention in Chronic Kidney Disease: Calls-to-Action from Nephrologists Based Mainly in Central/Eastern Europe.

BACKGROUND: Chronic kidney disease (CKD) has a global prevalence of 9.1-13.4%. Comorbidities are abundant and may cause and affect CKD. Cardiovascular disease strongly correlates with CKD, increasing the burden of both diseases. SUMMARY: As a group of 15 clinical nephrologists primarily practicing in 12 Central/Eastern European countries, as well as Israel and Kazakhstan, herein we review the significant unmet needs for patients with CKD and recommend several key calls-to-action. Early diagnosis and treatment are imperative to ensure optimal outcomes for patients with CKD, with the potential to greatly reduce both morbidity and mortality. Lack of awareness of CKD, substandard indicators of kidney function, suboptimal screening rates, and geographical disparities in reimbursement often hamper access to effective care. KEY MESSAGES: Our key calls-to-action to address these unmet needs, thus improving the standard of care for patients with CKD, are the following: increase disease awareness, such as through education; encourage provision of financial support for patients; develop screening algorithms; revisit primary care physician referral practices; and create epidemiological databases that rectify the paucity of data on early-stage disease. By focusing attention on early detection, diagnosis, and treatment of high-risk and early-stage CKD populations, we aim to reduce the burdens, progression, and mortality of CKD.

[Consensus recommendations on the diagnosis and treatment of hyponatremia from the Austrian Society for Nephrology 2024]. / Konsensusempfehlungen zur Diagnose und Therapie der Hyponatriämie der Österreichischen Gesellschaft für Nephrologie 2024.

Hyponatremia is a disorder of water homeostasis. Water balance is maintained by the collaboration of renal function and cerebral structures, which regulate thirst mechanisms and secretion of the antidiuretic hormone. Measurement of serum-osmolality, urine osmolality and urine-sodium concentration help to diagnose the different reasons for hyponatremia. Hyponatremia induces cerebral edema and might lead to severe neurological symptoms, which need acute therapy. Also, mild forms of hyponatremia should be treated causally, or at least symptomatically. An inadequate fast increase of the serum sodium level should be avoided, because it raises the risk of cerebral osmotic demyelination. Basic pathophysiological knowledge is necessary to identify the different reasons for hyponatremia which need different therapeutic procedures.

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 IgA Nephropathy-2023]. / Diagnostik und Therapie IgA Nephropathie ­ 2023.

Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis. It leads to end-stage kidney disease in about a third of the patients within 10 to 20 years. The pathogenesis of IgAN is incompletely understood. It is believed that a dysregulation of the mucosal immune system leads to undergalactosylation of IgA, followed by formation of IgG autoantibodies against undergalactosylated IgA, circulation of these IgG-IgA immune complexes, deposition of the immune complexes in the mesangium, ultimately resulting in glomerular inflammation. IgAN can occasionally be triggered by other diseases, these secondary causes of IgAN should be identified or ruled out (chronic inflammatory bowel disease, infections, tumors, rheumatic diseases). Characteristic findings of IgAN of variable extent are a nephritic urinary sediment (erythrocytes, acanthocytes, erythrocyte casts), proteinuria, impaired renal function, arterial hypertension, or intermittent painless macrohematuria, especially during infections of the upper respiratory tract. However, the diagnosis of IgAN can only be made by a kidney biopsy. A histological classification (MEST­C score) should always be reported to be able to estimate the prognosis. The most important therapeutic measure is an optimization of the supportive therapy, which includes, among other things, a consistent control of the blood pressure, an inhibition of the RAS, and the administration of an SGLT2 inhibitor. A systemic immunosuppressive therapy with corticosteroids is discussed controversially, should be used restrictively and only administered after an individual benefit-risk assessment under certain conditions that speak for a progressive IgAN. New promising therapeutics are enteral Budesonide or the dual angiotensin-II-receptor- and endothelin-receptor-antagonist Sparsentan. Rapidly progressive IgAN should be treated with corticosteroids and cyclophosphamide like ANCA-associated vasculitis.

[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 therapy of membranous nephropathy-2023]. / Diagnostik und Therapie der Membranösen Nephropathie ­ 2023.

Membranous nephropathy (MN) is an immune-complex glomerulonephritis and is one of the most common causes of nephrotic syndrome in adults and is also one of the autoimmune kidney diseases with the highest rate of spontaneous remission. The most common autoantigen (> 70% of cases) is directed against the phospholipase A2 receptor (PLA2-R) and, with its detection and clinical course, allows for excellent diagnostics as well as optimal therapy monitoring. Other autoantigens are constantly being published and will enable an autoantigen-based diagnostic and therapeutic algorithm for MN in the future. In the absence of spontaneous remission, a specific B­cell-directed therapy, especially with rituximab, is the initial therapy of choice. Calcineurininhibitors or cyclophosphamide should only be used if they are carefully indicated in the respective clinical context and if there are serious clinical consequences both from the nephrotic syndrome and from loss of kidney function. Since immune complexes within the kidney often require a long time to be degraded, proteinuria response can follow the immunological remission after many months. The therapy of MN represents the favorable case of a precision medicine-based therapy in nephrology, whereby new therapeutic B­cell antibodies for the rare but difficult forms of MN will find their way into clinical routine in the not-too-distant future.

[Diagnosis and treatment of focal-segmental glomerulosclerosis-2023]. / Diagnostik und Therapie der Fokal-Segmentalen Glomerulosklerose ­ 2023.

The histopathological term focal-segmental glomerulosclerosis comprises different pathogenic processes with the unifying features of a high proteinuria and the name-giving glomerular lesion pattern seen on light microscopy. A differentiation according to the underlying cause into primary, secondary and genetic forms is therefore of utmost importance. The pathogenesis of primary focal-segmental glomerulosclerosis remains unknown but, like minimal-change disease, an autoimmune-mediated process leading to podocyte damage is assumed. Consequently, the unifying term "podocytopathy" is increasingly being used for both entities. Supportive treatment measures to preserve kidney function are important in all subtypes. In contrast, immunosuppressive treatment is only indicated in primary focal-segmental glomerulosclerosis. Steroid-dependence, steroid-resistance and frequently relapsing disease often complicate disease management and necessitate alternative treatment strategies. Here, the Austrian Society of Nephrology (ÖGN) provides consensus recommendations on how to best diagnose and manage patients with focal-segmental glomerulosclerosis.

[Diagnostic and therapy of lupus nephritis - 2023]. / Diagnostik und Therapie der Lupusnephritis ­ 2023.

The manuscript summarizes the consensus of the Austrian Society of Nephrology on the diagnosis and therapy of lupusnephritis, which is built on existing studies and literature. We discuss in detail the immunosuppressive treatment in proliferative forms of lupusnephritis (III and IV ± V) and in pure lupusnephritis V with nephrotic-range proteinuria. Furthermore, the supportive medication in lupusnephritis is summarized in the consensus. The figures were designed to provide the reader a guidance through the therapeutical approach in lupusnephritis for the daily practice.

[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.

[General recommendations for the management of glomerular diseases-2023]. / Allgemeine Empfehlungen für die Behandlung glomerulärer Erkrankungen ­ 2023.

Glomerular diseases are associated with extrarenal complications, such as thromboembolism, cardiovascular events and particularly infections. A thorough knowledge of the various immunosuppressants and their associated toxicity profile is therefore of great importance. While nephrologists usually have extensive experience with calcineurin inhibitors and antimetabolites, two other compounds (rituximab, in severe cases cyclophosphamide) are used comparatively infrequently and will be discussed in more detail. Moreover, practical recommendations for the prevention of thromboembolism in states of nephrosis and for the prophylaxis of Pneumcystic jirovecii pneumonia are provided.

[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).

[Diabetic kidney disease (update 2023) : Position paper of the Austrian Diabetes Association and the Austrian Society for Nephrology]. / Diabetische Nierenerkrankung (Update 2023) : Positionspapier der Österreichischen Diabetes Gesellschaft und der Österreichischen Gesellschaft für Nephrologie.

Epidemiological investigations have shown that approximately 2-3% of all Austrians have diabetes mellitus with renal involvement, leaving 250,000 people in Austria affected. The risk of occurrence and progression of this disease can be attenuated by lifestyle interventions as well as optimization of blood pressure, blood glucose control and special drug classes. The present article represents the joint recommendations of the Austrian Diabetes Association and the Austrian Society of Nephrology for the diagnostic and treatment strategies of diabetic kidney disease.

Acute Kidney Injury and Mortality After Fenestrated Endovascular Aortic Repair.

INTRODUCTION: Acute kidney injury (AKI) is a common complication following endovascular aortic repair (EVAR). An association of AKI with patient survival after fenestrated EVAR (FEVAR) is currently under investigation. METHODS: Patients undergoing FEVAR between April 2013 and June 2020 were included in the study. AKI was defined according to acute kidney injury network criteria. Demographic and perioperative data, complications, and survival are reported for the study cohort. The data were analyzed to identify possible predictors of AKI. RESULTS: Two hundred and seventeen patients underwent FEVAR during the study period. Survival at last follow-up (20.4 ± 20.1 mo) was 75.1%. Thirty patients experienced AKI (13.8%). Six of 30 patients with AKI (20%) died within 30 days or in-hospital and 1 (3.3%) progressed to hemodialysis. Within 1 y, renal function had recovered in 23 patients (76.7%). In-hospital mortality was higher in patients with AKI (20% versus 4.3%, P = 0.006). A higher rate of AKI was seen in patients in whom an intraoperative technical complication had been documented (38.5% versus 8.4%, P = 0.001). CONCLUSIONS: Patients undergoing FEVAR are at risk of developing AKI, especially if they experience technical intraoperative complications. Most patients see recovery of renal function within the first 30 days to 1 y, but AKI remains associated with significantly increased in-hospital mortality.

Novel aspects in the pathophysiology and diagnosis of glomerular diseases.

Immune deposits/complexes are detected in a multitude of tissues in autoimmune disorders, but no organ has attracted as much attention as the kidney. Several kidney diseases are characterised by the presence of specific configurations of such deposits, and many of them are under a 'shared care' between rheumatologists and nephrologists. This review focuses on five different diseases commonly encountered in rheumatological and nephrological practice, namely IgA vasculitis, lupus nephritis, cryoglobulinaemia, anti-glomerular basement membrane disease and anti-neutrophil cytoplasm-antibody glomerulonephritis. They differ in disease aetiopathogenesis, but also the potential speed of kidney function decline, the responsiveness to immunosuppression/immunomodulation and the deposition of immune deposits/complexes. To date, it remains unclear if deposits are causing a specific disease or aim to abrogate inflammatory cascades responsible for tissue damage, such as neutrophil extracellular traps or the complement system. In principle, immunosuppressive therapies have not been developed to tackle immune deposits/complexes, and repeated kidney biopsy studies found persistence of deposits despite reduction of active inflammation, again highlighting the uncertainty about their involvement in tissue damage. In these studies, a progression of active lesions to chronic changes such as glomerulosclerosis was frequently reported. Novel therapeutic approaches aim to mitigate these changes more efficiently and rapidly. Several new agents, such as avacopan, an oral C5aR1 inhibitor, or imlifidase, that dissolves IgG within minutes, are more specifically reducing inflammatory cascades in the kidney and repeat tissue sampling might help to understand their impact on immune cell deposition and finally kidney function recovery and potential impact of immune complexes/deposits.

Value of SGLT-2 inhibitors in the treatment of chronic kidney disease : Clinical and practical implications.

Chronic kidney disease (CKD) drastically increases the risk for cardiovascular morbidity and mortality and its worldwide prevalence is still rising. Effective treatment slows CKD progression, prevents development of end-stage kidney disease and cardiovascular disease thereby prolonging survival of patients. Recently, several large-scale studies with sodium-glucose cotransport­2 inhibitors (SGLT-2i) have demonstrated profound nephroprotective and cardioprotective properties in patients with type 2 diabetes mellitus with both CKD and heart failure. Recently, the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial demonstrated that the selective SGLT-2i dapagliflozin reduced the hazard ratio for a composite renal and cardiovascular death endpoint in patients with CKD with or without type 2 diabetes. Furthermore, dapagliflozin exerted strong nephroprotection in CKD patients with diverse etiologies like IgA nephropathy. Furthermore, other promising CKD trials such as with empagliflozin are underway. Hence, individualized treatment with SGLT2i represents a promising therapeutic option for patients with both diabetic and non-diabetic CKD. Here we summarize the current knowledge on the treatment with SGLT-2i in CKD patients underscoring a strong rationale for SGLT2 inhibition to be incorporated into standard of care for most CKD patients also with non-diabetic kidney disease. Finally, we aim to translate the current evidence into recommendations for the clinical practice in the management of patients with CKD.

Growth differentiation factor-15 predicts major bleeding, major adverse cardiac events and mortality in patients with end-stage kidney disease on haemodialysis: findings from the VIVALDI study.

BACKGROUND: Patients with end-stage kidney disease (ESKD) are at high risk of cardiovascular events and bleeding. Optimizing risk assessment of ESKD patients regarding the risk of thromboembolism and bleeding complications in comorbid conditions, including atrial fibrillation and coronary heart disease, is challenging. To improve risk prediction we investigated growth differentiation factor-15 (GDF-15), a promising cardiovascular biomarker, and its relation to adverse outcomes. METHODS: In this prospective, multicentre, population-based cohort study, GDF-15 was measured in 594 ESKD patients on haemodialysis (median age 66 years, 38% female), who were followed up for a median of 3.5 years. The association of GDF-15 with major bleeding, arterial thromboembolism, major adverse cardiac events (MACE) and death was analysed within a competing risk framework. Further, we evaluated the additive predictive value of GDF-15 to cardiovascular and death risk assessment. RESULTS: GDF-15 levels were in median 5475 ng/l (25th-75th percentile 3964-7533) and independently associated with major bleeding {subdistribution hazard ratio [SHR] 1.31 per double increase [95% confidence interval (CI) 1.00-1.71]}, MACE [SHR 1.47 (95% CI 1.11-1.94)] and all-cause mortality [SHR 1.58 (95% CI 1.28-1.95)] but not arterial thromboembolism [SHR 0.91 (95% CI 0.61-1.36)]. The addition of GDF-15 to the HAS-BLED score significantly improved discrimination and calibration for predicting major bleeding [C-statistics increased from 0.61 (95% CI 0.52-0.70) to 0.68 (95% CI 0.61-0.78)]. Furthermore, we established an additive predictive value of GDF-15 beyond current risk models for predicting MACE and death. CONCLUSION: GDF-15 predicts the risk of major bleeding, cardiovascular events and death in ESKD patients on haemodialysis and might be a valuable marker to guide treatment decisions in this challenging patient population.