Glomerular diseases最新文献

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis can be a life-threatening condition, characterized by necrotizing inflammation of small blood vessels. Major organ involvement, most commonly kidney and lung disease, is associated with significant morbidity and mortality. Intensive early immunosuppressive therapy is the cornerstone of management and has transformed ANCA-associated vasculitis (AAV) into a chronic relapsing condition. Remission induction with tapering glucocorticoids in combination with cyclophosphamide or rituximab is the standard of care for severe disease. Avacopan, an oral C5aR1 antagonist, has been approved for remission induction and helps minimize glucocorticoid exposure. Plasma exchange should be considered for severe kidney or life-threatening disease. Lower dose glucocorticoid induction regimens can be used without compromising remission rates. Remission maintenance therapy is recommended, and rituximab is usually first line over azathioprine. Mycophenolate mofetil (MMF) or methotrexate with low-dose glucocorticoids are third-line options. Immunosuppression-associated infection risk remains a concern, both during acute presentations and in the long term, highlighted by the impact of rituximab on humoral immunity and vaccine response during the COVID-19 pandemic. There remains an ongoing need for therapies that induce rapid remission and optimize kidney recovery while minimizing infection risk. Clinical trials are evaluating newer therapeutic options. Due to increasing treatment options, management should be individualized, balancing effective immunosuppression against comorbidities and frailty.

Summary: This review focuses on the treatment decision pathways for clinicians and patients in the management of severe AAV (granulomatosis with polyangiitis and microscopic polyangiitis). Key clinical trials, predictors of outcome, novel therapeutics, and practical steps to mitigate infection risk are discussed.

Key messages: Immunosuppression regimens have been refined due to emerging evidence from clinical trials. Rituximab, avacopan, and reduced-dose glucocorticoid schedules have been the focus of recent studies. Infections and immunosuppression-induced immunodeficiency must be considered when determining individualized treatment.

Background: IgA nephropathy is the most common primary glomerular disease worldwide, and it is an important cause of end-stage kidney disease. Until recently, there were not any treatments of proven benefit, and care of patients with IgAN primarily involved supportive measures. Within the past few years, however, multiple new drugs have shown promise in clinical trials.

Summary: Among the new drugs, several complement inhibitory drugs have demonstrated efficacy at reducing proteinuria, and there is a strong rationale for expecting that these agents will be effective at slowing progression of the disease. Furthermore, anticomplement drugs target a part of the immune system that is not directly blocked by other classes of immunosuppressive agents. One of the new drugs, iptacopan, is a selective inhibitor of the alternative pathway. Preliminary results from a phase 3 study of iptacopan in IgA nephropathy demonstrated that treatment is associated with a rapid reduction in proteinuria, and the drug recently received accelerated approval from the Food and Drug Administration. Additional drugs that have been tested in IgA nephropathy include agents that block the complement cascade at the levels of C3 and C5. Complement activation in the kidneys of IgA nephropathy patients generates biomarkers that can be detected in the blood, urine, and kidney biopsies. If multiple complement inhibitory drugs receive approval for IgA nephropathy, these biomarkers may be useful for selecting the most appropriate drug for an individual patient. Complement biomarkers may also be useful for monitoring a patient's response to treatment.

Key messages: Several complement inhibitors are currently in clinical trials for IgAN. Iptacopan recently received accelerated approval for the indication and complement inhibitory drugs will likely become an integral part of the treatment for this disease in the near future. As these drugs become available in the clinic, it will be important to develop biomarkers that can guide clinicians to the best drug for an individual patient.

Background: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) frequently affects the kidney. Glomerulonephritis (GN) in AAV, ANCA-GN, not only dictates therapeutic decisions but is also of relevance for overall survival influencing the risk of cardiovascular disease and serious infections.

Summary: A diagnosis of ANCA-GN includes laboratory investigations including urinalysis and a thorough assessment of potential organ involvement. A kidney biopsy can be performed to ascertain the diagnosis but has an additional prognostic relevance and tools have been established to predict long-term kidney survival. Experimental biomarkers indicating kidney inflammation include urinary soluble CD163 and the presence of urinary T cells. Therapeutic options are refined and some of these therapies, such as the added value of performing plasma exchange, are the matter of controversial discussions. Safe reduction of cumulative exposure to glucocorticoids and eventually the use of avacopan to substantially reduce glucocorticoid exposure has been implemented in most centers. In the remission of maintenance, the optimal duration of therapy is still unclear, but extended use of rituximab as maintenance agent has shown long-term remission rates, thus limiting the damage accrued by relapsing disease and thus also reducing the risk of end-stage kidney disease (ESKD). Avacopan has been the first agent with a glomerular filtration rate-sparing effect, likely due to more rapid control of kidney inflammation. Those reaching ESKD should be evaluated for kidney transplantation and the risk of remaining on dialysis must be balanced against the risk of recurrence of disease following transplantation.

Key messages: The advent of a magnitude of landmark studies in ANCA-GN has refined diagnostic approaches, implemented tools to predict kidney outcome, and eventually led to the approval of newer therapies with avacopan, the latest addition to the armamentarium. Once ESKD is present, patients should be considered for kidney transplantation as remaining on dialysis portends poor overall prognosis.

Introduction: The morbidity of recurrent focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) after transplant is well recognized. Additional collaborative research is necessary to advance understanding of recurrence epidemiology, mechanisms, interventions, and outcomes, particularly in children.

Methods: RESOLVE is a multicenter, observational cohort study examining the posttransplant course of patients with FSGS and MCD across the lifespan. Multiple enrollment options will facilitate both retrospective and prospective collection of biospecimens, self-report items, and electronic health record data across pediatric and adult participants. The study offers a unique mobile health option for participants to enroll and engage with the study remotely. Logistic regression using a log link function will evaluate recurrence risk within 3 months of transplant based on clinical characteristics and assess the impact of social determinants of health on time to graft failure, following adjustment. Cox proportional hazards models with primary outcome of graft failure with competing risk of death will evaluate the impact of recurrence therapy and access to preventative versus reactive recurrence therapy. Independent logistic regression will evaluate the impact of recurrence therapy and endophenotypes on proteinuric outcomes.

Conclusion: Multiple enrollment approaches and tailored site participation are needed while studying recurrent FSGS (rFSGS) due to its rarity and phenotypic variability. RESOLVE provides a framework for international collaboration to unravel the course of rFSGS through a biospecimen and data repository. It also explores the potential for mobile health tools to enhance recruitment of participants and to promote cooperation among researchers to advance understanding of recurrence mechanisms and treatments.

Introduction: Concurrent atypical anti-glomerular basement membrane (anti-GBM) disease with membranous nephropathy is a rare occurrence. Compared to typical anti-GBM disease, atypical anti-GBM disease is often seronegative, with a mild disease presentation and course. We present a case of concomitant of PLA2R-associated membranous nephropathy and atypical anti-GBM disease in a patient with cholangiocarcinoma.

Case presentation: A 66-year-old male with type 2 diabetes, hypertension, hyperlipidemia, hepatitis C, cirrhosis, and cholangiocarcinoma presented with nephrotic range proteinuria and worsening bilateral lower extremity edema. Urine studies showed 3+ protein and 13 red blood cells per high power field and 24-h urine protein of 14 g (nephrotic range). Serum albumin was 2.1 g/dL and serum creatinine was 0.8 mg/dL (nephrotic syndrome). Serological work-up was negative for antinuclear antibody, anti-double stranded DNA antibody, anti-PLA2R, anti-neutrophil cytoplasmic antibody, rheumatoid factor, and anti-GBM. Complement (C3 and C4) levels were normal and no monoclonal gammopathy was detected. A kidney biopsy showed membranous nephropathy with typical light microscopic, immunofluorescence, and electron microscopic findings. In addition, there was atypical anti-GBM disease characterized by a non-circumferential cellular crescent in 1 out of 12 glomeruli 2-3+ linear staining for IgG along GBM. There was no tubular basement membrane staining for IgG and albumin staining was negative. The glomeruli demonstrated strong staining for PLA2R but were negative for THSD7A and NELL-1. The patient received rituximab infusion, dapagliflozin, and lisinopril, resulting in remission of proteinuria. Despite intense chemotherapy with cisplatin, gemcitabine, and immunotherapy, the patient's cholangiocarcinoma progressed, and he transitioned to hospice care.

Conclusion: For our patient, rituximab resulted in remission of proteinuria. The lack of temporal association with the malignancy is consistent with the biopsy findings of PLA2R-associated membranous nephropathy. While there is not an established guideline for atypical anti-GBM disease, our case demonstrates the utility of rituximab for the management of concurrent atypical anti-GBM disease with membranous nephropathy.

Background: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are major forms of nephrotic syndrome that remain difficult to treat. MCD and FSGS have distinct but also overlapping clinical, histological, metabolic, and molecular features. Effective use of immunosuppressive drugs, activated immune cells, altered cytokine profiles, and upregulated signaling pathways suggest a link between immune dysfunction and nephrotic syndrome, but the exact mechanism of immunopathogenesis is unclear. Immune dysfunction is an area of ongoing research for identifying novel molecular targets for treating nephrotic syndrome. However, the available animal models do not directly address the role of immune dysfunction in nephrotic syndrome.

Summary: Genetic analysis indicates that heterogeneous genes related to the podocyte-specific proteins may indirectly cause damage to filtration barrier and influence the onset and progression of nephrotic syndrome. SH3BP2 protein regulates several pathways through its role as a scaffold for many signaling mediators and enzymes. SH3BP2 is expressed in immune as well as in nonimmune cells including podocytes. The role of SH3BP2 is discussed in the context of cells and molecules of adaptive and innate immune systems. Available information on the importance of SH3BP2 in diseases other than nephrotic syndrome and its role in the immunopathogenesis of human nephrotic syndrome are summarized. We outline the key features of a transgenic mouse strain with a gain-in-function mutation (Sh3bp2 ^KI/KI ) as a potential model to study immunopathogenesis of nephrotic syndrome.

Key messages: Non-receptor, non-catalytic proteins such as SH3BP2 are a novel group of proteins that regulate the innate and adaptive immune responses in nephrotic syndrome. New evidence suggests a critical role of SH3BP2 in immunopathogenesis of nephrotic syndrome. Our recent results demonstrate that transgenic mice (Sh3bp2 ^KI/KI ) with a gain-in-function mutation will likely be a unique model to study immunopathogenesis of nephrotic syndrome.

Background: Diabetic kidney disease (DKD) is a global health issue. Epigenetic changes play an important role in the pathogenesis of this disease.

Summary: DKD is currently the leading cause of kidney failure worldwide. Although much is known about the pathophysiology of DKD, the research field of epigenetics is relatively new. Several recent studies have demonstrated that diabetes-induced dysregulation of epigenetic mechanisms alters the expression of pathological genes in kidney cells. If these changes persist for a long time, the so-called "metabolic memory" could be established. In this review, we highlight diabetes-induced epigenetic modifications associated with DKD. While there is a substantial amount of literature on epigenetic changes, only a few studies describe the underlying molecular mechanisms. Detailed analyses have shown that epigenetic changes play an important role in known pathological features of DKD, such as podocyte injury, fibrosis, accumulation of extracellular matrix, or oxidative injury, all of which contribute to the pathophysiology of disease. The transforming growth factor-β plays a key role as it is involved in all-mentioned epigenetic types of regulation.

Key messages: Epigenetic is crucial for the development and progression of DKD, but the detailed molecular mechanisms have to be further analyzed more in detail.

Background: Immunofluorescence (IF) studies play an essential role in the evaluation of medical renal biopsies. Particularly, in the study of renal glomerular diseases, where it provides fundamental data for the diagnosis, classification, and etiology of the glomerular pathologies. Diverse techniques may be used to optimize the utilization of IF studies, from variations on the test methodologies to expertise on the interpretation of the results and knowledge of potential pitfalls.

Summary: This manuscript presents a brief review on the history of IF and its utilization in kidney pathology, followed by a description of the IF methods, including the use of IF on paraffin-embedded tissue (paraffin IF), and other novel techniques. Guidelines on how to best report IF findings are reviewed, along with a description of antibodies commonly used in glomerular diseases, highlighting their distribution within the normal kidney and potential pitfalls in interpretation. Finally, the use and interpretation of IF are discussed in more detail in individual entities on a range of glomerular diseases.

Key messages: IF is crucial for interpretation of renal biopsies and diagnosis of glomerular diseases. Knowledge of IF techniques, alternative procedures, its use and proper interpretation is essential for optimal utilization of IF in renal pathology, and this review proposes to serve as a simplified and practical guide on this topic.

Background: Complement 3 (C3) glomerulopathy (C3G) is a heterogenous disease characterized by dysregulation of the complement alternative pathway. Within 10 years of a diagnosis, roughly 50% of patients with C3G will progress to end-stage kidney disease. Historically, treatment options have been limited to nonspecific immune suppression with suboptimal response rates to recommended therapies. Advances in immunology and the emergence of novel complement-targeted therapies have shifted the focus toward identifying the distinct underlying etiologies of C3G.

Summary: In this review, we provide a description of the current landscape and challenges faced in the classification, evaluation, and treatment of patients with C3G.

Key message: C3G can be broadly separated into four distinct groups: (1) genetic mutations/variants, (2) autoimmune/acquired autoantibodies, (3) monoclonal immunoglobulin-associated C3G, and (4) C3G without an identified cause. Therapy directed toward the underlying pathogenetic cause of C3G may improve outcomes in a disease in which current treatment options are largely ineffective.

Background: Pauci-immune glomerulonephritis (PIGN) is typically secondary to antineutrophil cytoplasmic antibodies (ANCA) small-vessel vasculitis. However, some cases lack detectable circulating ANCA and are called ANCA-negative PIGN (seronegative PIGN). The reported incidence of this varies greatly. Its relationship to ANCA-associated vasculitis (AAV) is unclear.

Summary: This review explores the pathophysiology of seronegative PIGN and summarizes findings from 12 studies focusing on this disease. The role of neutrophils appears to be central, with activation through cellular and humoral mechanisms. Most studies have noted less extrarenal involvement and more chronic changes in the kidney biopsy in seronegative PIGN compared to ANCA-positive cases. Studies have mostly reported using corticosteroids with cyclophosphamide for induction therapy and azathioprine for maintenance. The renal survival was noted to be lower compared to ANCA-positive PIGN.

Key messages: Whether ANCA-negative PIGN represents a distinct disease or is part of the AAV spectrum remains unclear. Prospective large-scale studies are needed to understand this disease for optimal diagnosis and management.