A Focus Group Study of Self-Management in Patients With Glomerular Disease.

INTRODUCTION: Patients with glomerular disease experience symptoms that impair their physical and mental health while managing their treatments, diet, appointments and monitoring general and specific indicators of health and their illness. We sought to describe the perspectives of patients and their care partners on self-management in glomerular disease. METHODS: We conducted 16 focus groups involving adult patients with glomerular disease (n = 101) and their care partners (n = 34) in Australia, Hong Kong, the United Kingdom, and United States. Transcripts were analyzed thematically. RESULTS: We identified the following 4 themes: empowered in autonomy (gaining confidence through understanding, taking ownership of disease and treatment, learning a positive health approach); overwhelmed by compounding treatment burdens (financially undermined and depleted, demoralized by side effects and harms, frustrated by fragmented and inflexible care, fear of possible drug harms); striving for stability and normalcy (making personal sacrifices, maximizing life participation, attentiveness to bodily signs, avoiding precarious health states, integrating medicines into routines); and necessity of health-sustaining relationships (buoyed by social support, fulfilling meaningful responsibilities, sharing and normalizing experiences, seeking a trusting and respectful alliance). CONCLUSION: Patients with glomerular disease and their care partners value their capacity for autonomy and disease ownership, stability of their health, and relationships that support self-management. Strategies directed at strengthening these factors may increase self-efficacy and improve the care and outcomes for patients with glomerular disease.

A Core Outcome Set for Trials in Glomerular Disease: A Report of the Standardized Outcomes in Nephrology-Glomerular Disease (SONG-GD) Stakeholder Workshops.

BACKGROUND AND OBJECTIVES: Outcomes reported in trials in adults with glomerular disease are often selected with minimal patient input, are heterogeneous, and may not be relevant for clinical decision making. The Standardized Outcomes in Nephrology-Glomerular Disease (SONG-GD) initiative aimed to establish a core outcome set to help ensure that outcomes of critical importance to patients, care partners, and clinicians are consistently reported. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: We convened two 1.5-hour workshops in Melbourne, Australia, and Washington, DC, United States. Attendees were identified purposively with 50 patients/care partners and 88 health professionals from 19 countries; 51% were female. Patients and care partners were from the United States, Australia, and Canada, and had experience of a glomerular disease with systemic features (n=9), kidney-limited nephrotic disease (n=9), or other kidney-limited glomerular disease (n=8). Attendees reviewed the results of the SONG-GD Delphi survey and aims of the workshop and then discussed potential core outcomes and their implementation in trials among moderated breakout groups of eight to 12 people from diverse backgrounds. Transcripts of discussions were analyzed thematically. RESULTS: Three themes were identified that supported the proposed core outcomes: limiting disease progression, stability and control, and ensuring universal relevance (i.e., applicable across diverse populations and settings). The fourth theme, preparedness for implementation, included engaging with funders and regulators, establishing reliable and validated measures, and leveraging existing endorsements for patient-reported outcomes. CONCLUSIONS: Workshop themes demonstrated support for kidney function, disease activity, death, life participation, and cardiovascular disease, and these were established as the core outcomes for trials in adults with glomerular disease. Future work is needed to establish the core measures for each domain, with funders and regulators central to the uptake of the core outcome set in trials.

Improving Clinical Trials for Anticomplement Therapies in Complement-Mediated Glomerulopathies: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Blocking the complement system as a therapeutic strategy has been proposed for numerous glomerular diseases but presents myriad questions and challenges, not the least of which is demonstrating efficacy and safety. In light of these potential issues and because there are an increasing number of anticomplement therapy trials either planned or under way, the National Kidney Foundation facilitated an all-virtual scientific workshop entitled "Improving Clinical Trials for Anti-Complement Therapies in Complement-Mediated Glomerulopathies." Attended by patient representatives and experts in glomerular diseases, complement physiology, and clinical trial design, the aim of this workshop was to develop standards applicable for designing and conducting clinical trials for anticomplement therapies across a wide spectrum of complement-mediated glomerulopathies. Discussions focused on study design, participant risk assessment and mitigation, laboratory measurements and biomarkers to support these studies, and identification of optimal outcome measures to detect benefit, specifically for trials in complement-mediated diseases. This report summarizes the discussions from this workshop and outlines consensus recommendations.

Recurrent Glomerular Disease after Kidney Transplantation: Diagnostic and Management Dilemmas.

Recurrent glomerular disease after kidney transplant remains an important cause of allograft failure. Many of the different entities post-transplant still suffer from incomplete knowledge on pathophysiology, and therefore lack targeted and effective therapies. In this review, we focus on specific clinical dilemmas encountered by physicians in managing recurrent glomerular disease by highlighting new insights into the understanding and treatment of post-transplant focal segmental glomerulosclerosis, membranous nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, amyloid light-chain (AL) amyloidosis, and IgA nephropathy.

Development of an international Delphi survey to establish core outcome domains for trials in adults with glomerular disease.

Outcomes relevant to treatment decision-making are inconsistently reported in trials involving glomerular disease. Here, we sought to establish a consensus-derived set of critically important outcomes designed to be reported in all future trials by using an online, international two-round Delphi survey in English. To develop this, patients with glomerular disease, caregivers and health professionals aged 18 years and older rated the importance of outcomes using a Likert scale and a Best-Worst scale. The absolute and relative importance was assessed and comments were analyzed thematically. Of 1198 participants who completed Round 1, 734 were patients/caregivers while 464 were health care professionals from 59 countries. Of 700 participants that completed Round 2, 412 were patients/caregivers and 288 were health care professionals. Need for dialysis or transplant, kidney function, death, cardiovascular disease, remission-relapse and life participation were the most important outcomes to patients/caregivers and health professionals. Patients/caregivers rated patient-reported outcomes higher while health care professionals rated hospitalization, death and remission/relapse higher. Four themes explained the reasons for their priorities: confronting death and compounded suffering, focusing on specific targets in glomerular disease, preserving meaning in life, and fostering self-management. Thus, consistent reporting of these critically important outcomes in all trials involving glomerular disease is hoped to improve patient-centered decision-making.

Bevacizumab-associated thrombotic microangiopathy treated with eculizumab: A case series and systematic review of the literature.

BACKGROUND: Bevacizumab is a recombinant monoclonal antibody against the vascular endothelial growth factor A (VEGF-A) ligand that is used in the management of various solid malignancies. The adverse effect profiles of angiogenesis inhibitors, such as bevacizumab, have become increasingly well characterized and include renal manifestations such as hypertension, proteinuria, and thrombotic microangiopathy. Eculizumab inhibits terminal-complement activation and is used to treat atypical hemolytic uremic syndrome. There has been growing usage of eculizumab to treat bevacizumab-associated thrombotic microangiopathy. MATERIALS AND METHODS: We performed a systematic review of the literature to identify full-text articles that describe the use of eculizumab for bevacizumab-associated thrombotic microangiopathy. RESULTS: Our systematic review identified 522 unique articles of which 5 were included in the final review. 9 cases, including 2 new cases presented in this review, were identified in which eculizumab was used in the management of bevacizumab-associated thrombotic microangiopathy. Hematologic parameters and kidney function stabilized or improved in all cases, and the 2 patients who required renal replacement therapy were able to discontinue dialysis. CONCLUSIONS: Given the findings of this systematic review, the use of eculizumab in the treatment of bevacizumab-associated thrombotic microangiopathy warrants further study, particularly in severe cases.

The Clone Wars: Diagnosing and Treating Dysproteinemic Kidney Disease in the Modern Era.

Dysproteinemic kidney diseases are disorders that occur as the result of lymphoproliferative (B cell or plasma cell) disorders that cause kidney damage via production of nephrotoxic monoclonal immunoglobulins or their components. These monoclonal immunoglobulins have individual physiochemical characteristics that confer specific nephrotoxic properties. There has been increased recognition and revised characterization of these disorders in the last decade, and in some cases, there have been substantial advances in disease understanding and treatments, which has translated to improved patient outcomes. These disorders still present challenges to nephrologists and patients, since they are rare, and the field of hematology is rapidly changing with the introduction of novel testing and treatment strategies. In this review, we will discuss the clinical presentation, kidney biopsy features, hematologic characteristics and treatment of dysproteinemic kidney diseases.

APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis.

BACKGROUND: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging. METHODS: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. RESULTS: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. CONCLUSIONS: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.

Kidney injury and disease in patients with haematological malignancies.

Acute kidney injury (AKI) is common in patients with cancer, especially in those with haematological malignancies. Kidney injury might be a direct consequence of the underlying haematological condition. For example, in the case of lymphoma infiltration or extramedullary haematopoiesis, it might be caused by a tumour product; in the case of cast nephropathy it might be due to the presence of monoclonal immunoglobulin; or it might result from tumour complications, such as hypercalcaemia. Kidney injury might also be caused by cancer treatment, as many chemotherapeutic agents are nephrotoxic. High-intensity treatments, such as high-dose chemotherapy followed by haematopoietic stem cell transplantation, not only increase the risk of infection but can also cause AKI through various mechanisms, including viral nephropathies, engraftment syndrome and sinusoidal obstruction syndrome. Some conditions, such as thrombotic microangiopathy, might also result directly from the haematological condition or the treatment. Novel immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T cell therapy, can also be nephrotoxic. As new therapies for haematological malignancies with increased anti-tumour efficacy and reduced toxicity are developed, the number of patients receiving these treatments will increase. Clinicians must gain a good understanding of the different mechanisms of kidney injury associated with cancer to better care for these patients.

Untangling immunotactoid glomerulopathy in the MGRS era.

Immunotactoid glomerulopathy (ITG) is a rare disease diagnosed by kidney biopsy showing characteristic microtubules, often in parallel arrays, in glomeruli on electron microscopy. Most cases are caused by lymphoproliferative disorders that produce monoclonal immunoglobulins that cause kidney damage, but these disorders do not meet criteria for overt malignancy. The published literature on ITG is limited. In this issue of Kidney International, 2 manuscripts provide significant insight into the clinical presentation, pathology, and treatment of ITG.

Bortezomib Treatment for Refractory PLA2R-Positive Membranous Nephropathy.

Introduction: B-cell depletion has been shown to be an effective strategy for the majority of patients with membranous nephropathy (MN), and in PLA2R-positive MN, immunologic remission (improvement or elimination of measurable serum anti-PLA2R antibodies) precedes renal remission. Yet, cases exist of patients who do not achieve immunologic remission despite achieving peripheral B-cell depletion. This has led to the hypothesis that some patients have plasma cells that are responsible for producing anti-PLA2R antibodies. Case Presentation: A 66-year-old man with a past medical history of hypertension, hyperlipidemia, and cerebrovascular disease presented with nephrotic syndrome and was diagnosed with PLA2R-positive MN on kidney biopsy. He was refractory to multiple therapies including tacrolimus, and was resistant to rituximab despite having achieved B-cell depletion. He also did not enter into remission with plasmapharesis and cyclophosphamide. He then achieved immediate immunologic remission after treatment with the proteasome inhibitor bortezomib, which is used as first-line therapy for multiple myeloma. Discussion/Conclusion: This case suggests that considering the source of PLA2R antibody production could lead to individualized and targeted therapies for MN.

Persistent Disease Activity in Patients With Long-Standing Glomerular Disease.

INTRODUCTION: Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease. METHODS: Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort, n = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy <5 years before enrollment drawn from the Cure Glomerulonephropathy Network (CureGN cohort, n = 1182; CUMC-CureGN cohort, n = 362). Disease activity was defined by (i) Kidney Disease: Improving Global Outcomes-recommended threshold criteria for initiation of immunosuppression in primary glomerulonephropathy (GN) and (ii) CureGN's Disease Activity Working Group definitions for activity. RESULTS: No significant differences were detected among the 3 cohorts in terms of age, sex, serum creatinine, and urinary protein-to-creatinine ratio. For each GN subtype, disease activity in the OLD cohort was comparable with disease activity in the entire CureGN and the CUMC-CureGN cohort. When limiting our comparisons to disease activity in incident CUMC-CureGN patients (first diagnostic biopsy within 6 months of enrollment), OLD patients demonstrated similar activity rates as incident patients. CONCLUSION: Disease activity did not differ among patients with shorter versus longer duration of disease. Such survivor patients, with long-term but persistent disease, are potentially highly informative for understanding the clinical course and pathogenesis of GN and may help identify factors mediating more chronic subtypes of disease.

Identifying Outcomes Important to Patients with Glomerular Disease and Their Caregivers.

BACKGROUND AND OBJECTIVES: Shared decision making in patients with glomerular disease remains challenging because outcomes important to patients remain largely unknown. We aimed to identify and prioritize outcomes important to patients and caregivers and to describe reasons for their choices. DESIGN: , setting, participants, & measurementsWe purposively sampled adult patients with glomerular disease and their caregivers from Australia, Hong Kong, the United Kingdom, and the United States. Participants identified, discussed, and ranked outcomes in focus groups using the nominal group technique; a relative importance score (between zero and one) was calculated. Qualitative data were analyzed thematically. RESULTS: Across 16 focus groups, 134 participants (range, 19-85 years old; 51% women), including 101 patients and 33 caregivers, identified 58 outcomes. The ten highest-ranked outcomes were kidney function (importance score of 0.42), mortality (0.29), need for dialysis or transplant (0.22), life participation (0.18), fatigue (0.17), anxiety (0.13), family impact (0.12), infection and immunity (0.12), ability to work (0.11), and BP (0.11). Three themes explained the reasons for these rankings: constraining day-to-day experience, impaired agency and control over health, and threats to future health and family. CONCLUSIONS: Patients with glomerular disease and their caregivers highly prioritize kidney health and survival, but they also prioritize life participation, fatigue, anxiety, and family impact.

Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone.

IgG (mainly IgG3) is the most commonly involved isotype in proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Here we describe the first series of PGNMID with deposition of monoclonal immunoglobulin light chain only (PGNMID-light chain). This multicenter cohort of 17 patients presented with nephritic or nephrotic syndrome with underlying hematologic conditions of monoclonal gammopathy of renal significance (71%) or multiple myeloma (29%). Monoclonal immunoglobulin was identified by serum and urine immunofixation in 65% and 73%, respectively, with abnormal serum free light chain in 83%, and a detectable bone marrow plasma cell clone in 88% of patients. Renal biopsy showed a membranoproliferative pattern in most patients. By immunofluorescence, deposits were restricted to glomeruli and composed of restricted light chain (kappa in 71%) and C3, with granular appearance and subendothelial, mesangial and subepithelial distribution by electron microscopy. Proteomic analysis in four cases of kappa PGNMID-light chain revealed spectra for kappa constant and variable domains, without evidence of Ig heavy chains; spectra for proteins of the alternative pathway of complement and terminal complex were detected in three. The classical pathway was not detected in three cases. After median follow up of 70 months, the renal response was dependent on a hematologic response and occurred in six of ten patients treated with plasma cell-directed chemotherapy but none of five patients receiving other therapies. Thus, PGNMID-light chain differs from PGNMID-IgG by higher frequency of a detectable pathogenic plasma cell clone. Hence, proper recognition is crucial as anti-myeloma agents may improve renal prognosis. Activation of an alternative pathway of complement by monoclonal immunoglobulin light chain likely plays a role in its pathogenesis.