[Role of Complement in Kidney Diseases - New Aspects]. / Die Rolle des Komplementsystems bei Nierenerkrankungen ­ Neue Aspekte.

Complement is a central part of the immune system. In the human body, complement is responsible for recognition of infectious microbes, for coordinating the adaptive immune response, controlling homeotic reactions and for the non-inflammatory removal of modified self-cells and infectious microbes. Complement is also closely linked to another proteolytic cascade, the coagulation system. Defective activation and altered complement regulation drives pathology of several severe human kidney diseases.This manuscript summarizes the latest developments on the role of complement in kidney diseases, on new complement inhibitors and on recent complement targeting therapies. In particular focusing on diseases (1) atypical Hemolytic Uremic Syndrome, (2) C3 Glomerulopathy, (3) Anti Neutrophil Cytoplasmic Antibody Mediated Vasculitis, (4) IgA Nephropathy, (5) Membranous Glomerulopathy, (6) Systemic Lupus Erythematosus, (7) Transplant rejection and (8) COVID 19 Infection-Triggered Kidney Diseases. More excitement is generated in this field, as more and more complement mediated diseases can be treated. Several complement targeting compounds are approved by the EMA and FDA and an increasing number of new candidates are in late phase clinical trials. In addition, clinical guidelines are developed for Diagnosis and Therapy of complement mediated diseases, new biomarkers are evaluated in clinical studies, and diagnostic guidelines are in development. The recent Covid infections showed a clear link of complement in thrombo inflammation, which ultimately results in kidney damage. These aspects have increased further the focus of complement inhibitors in COVID infections.

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial.

BACKGROUND: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. METHODS: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to <60 mL/min per 1·73 m2 and ≥60 mL/min per 1·73 m2) and urine protein excretion at screening (≤1·75 g/day and >1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. INTERPRETATION: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. FUNDING: Travere Therapeutics.

Rapidly progressive IgA nephropathy with membranoproliferative glomerulonephritis-like lesions in an elderly man following the third dose of an mRNA COVID-19 vaccine: a case report.

BACKGROUND: As messenger RNA (mRNA)-based vaccines for coronavirus disease 2019 (COVID-19) have been administered to millions of individuals worldwide, cases of de novo and relapsing glomerulonephritis after mRNA COVID-19 vaccination are increasing in the literature. While most previous publications reported glomerulonephritis after the first or second dose of an mRNA vaccine, few reports of glomerulonephritis occurring after the third dose of an mRNA vaccine currently exist. CASE PRESENTATION: We report a case of rapidly progressive glomerulonephritis in a patient following the third dose of an mRNA COVID-19 vaccine. A 77-year-old Japanese man with a history of hypertension and atrial fibrillation was referred to our hospital for evaluation of anorexia, pruritus, and lower extremity edema. One year before referral, he received two mRNA vaccines (BNT162b2) for COVID-19. Three months before the visit, he received a third mRNA vaccine (mRNA-1273) for COVID-19. On admission, the patient presented severe renal failure with a serum creatinine level of 16.29 mg/dL, which had increased from 1.67 mg/dL one month earlier, prompting us to initiate hemodialysis. Urinalysis showed nephrotic-range proteinuria and hematuria. Renal biopsy revealed mild mesangial proliferation and expansion, a lobular appearance, and double contours of the glomerular basement membrane. Renal tubules had severe atrophy. Immunofluorescence microscopy showed strong mesangial staining for IgA, IgM, and C3c. Electron microscopy exhibited mesangial and subendothelial electron-dense deposits, leading to a diagnosis of IgA nephropathy with membranoproliferative glomerulonephritis-like changes. The kidney function remained unchanged after steroid therapy. CONCLUSIONS: Although the link between renal lesions and mRNA vaccines remains unclear, a robust immune response induced by mRNA vaccines may play a role in the pathogenesis of glomerulonephritis. Further studies of the immunological effects of mRNA vaccines on the kidney are warranted.

New insights into the mucosal immune pathogenesis of IgA nephropathy from the perspective of COVID-19 vaccination.

Large-scale SARS-CoV-2 vaccination is one of the key strategies to curb the COVID-19 pandemic; however, there are increasing reports of IgA nephropathy following COVID-19 vaccination. The clinical manifestation, treatment and prognostic effects are different in IgAN patients who have had an onset after the first and second dose of vaccination, as well as new and recurrent IgAN patients. These conditions bring about a relatively important window for understanding the pathogenesis of IgAN. Gd-IgA1 is the core of the pathogenesis of IgAN. Most IgA is produced at mucosal sites; however, antigen-activated Toll-like receptor activation pathways expressed by antigen-presenting cells and B-cell homing receptors are different in the intestinal and respiratory mucosa, and the link between respiratory and intestinal mucosa is not well understood in the pathogenesis of IgAN. Budesonide treatment of IgAN is thought to inhibit the intestinal immune response by binding to glucocorticoid receptors in the intestinal mucosa or submucosa; however, it is unclear whether there is a therapeutic effect in respiratory mucosa-derived IgA nephropathy. The present review firstly described the relationship between the gut and respiratory mucosa, and the differences in antigen-presenting cell activation pathways and B-cell homing from the perspective of COVID-19 vaccines.

Identification of IgA autoantibodies targeting mesangial cells redefines the pathogenesis of IgA nephropathy.

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis, often progressing to renal failure. IgAN is triggered by IgA deposition in the glomerular mesangium by an undefined mechanism. Here, we show that grouped ddY (gddY) mice, a spontaneous IgAN model, produce serum IgA against mesangial antigens, including ßII-spectrin. Most patients with IgAN also have serum anti-ßII-spectrin IgA. As in patients with IgAN, IgA+ plasmablasts accumulate in the kidneys of gddY mice. IgA antibodies cloned from the plasmablasts carry substantial V-region mutations and bind to ßII-spectrin and the surface of mesangial cells. These IgAs recognize transfected and endogenous ßII-spectrin exposed on the surface of embryonic kidney-derived cells. Last, we demonstrate that the cloned IgA can bind selectively to glomerular mesangial regions in situ. The identification of IgA autoantibody and its antigen in IgAN provides key insights into disease onset and redefines IgAN as a tissue-specific autoimmune disease.

Renal biopsy in systemic infections: expect the unexpected.

Infection-related glomerulonephritis is well recognized in patients with ongoing infections. It can be missed, however, if the infection is unusual or undetected. We present three cases where the renal biopsy findings prompted the identification or treatment of systemic infections.Case 1: A 84-year-old male presented with acute kidney injury (AKI) and IgA vasculitis on skin biopsy. A renal biopsy showed active glomerulonephritis with abundant neutrophils and predominantly mesangial immune complex deposits containing IgA. The findings prompted an infectious workup which was positive for COVID-19, suggesting exacerbation of IgA nephropathy by recent COVID-19 infection. Case 2: A 31-year-old female status post kidney transplant for granulomatosis with polyangiitis (GPA) had recent pregnancy with preterm delivery, disseminated herpes simplex virus (HSV) infection with HSV hepatitis, E. coli on urine culture, and AKI. A renal biopsy showed proliferative glomerulonephritis with subendothelial and mesangial immune complex deposits containing IgG and C3. The findings were most consistent with infection-related immune complex glomerulonephritis, most likely HSV-related. Case 3: A 78-year-old female presented with AKI, proteinuria, hematuria, and positive p-ANCA. Clinically, ANCA vasculitis was suspected, and renal biopsy did show focal, segmental, necrotizing glomerulonephritis. However, immunofluorescence and electron microscopy showed IgM-rich deposits in the mesangium. The unusual presentation prompted an infectious workup including a Bartonella antibody panel which showed very high titers, suggesting Bartonella endocarditis.Infection-related glomerulonephritis has a wide variety of presentations histologically and clinically. The three cases we present here emphasize the importance of recognizing these entities to help guide treatment and improve patient care.

Gross hematuria and IgA nephropathy flare-up following the first dose of Moderna vaccine: A case report.

BACKGROUND: Since the mass vaccination for COVID-19, several case reports indicated the risk of autoimmune disease flare-ups after the vaccination. Among them, COVID-19 vaccine-induced glomerular diseases have drawn attention worldwide. The cases demonstrating the association between the mRNA vaccine and IgA nephropathy (IgAN) exacerbation had been noticed. Mostly mentioned, the flare-ups usually occurred after the second dose. METHODS: We present a Taiwanese female with IgAN who developed gross hematuria within only six hours after the first dose of the Moderna vaccine. RESULTS: Six hours after the first dose of Moderna vaccine on 8 June 2021, the patient developed gross hematuria and significantly decreased urine output. All symptoms resolved spontaneously on the fifth day after the vaccination without any intervention. On the fourth day after the vaccination, the patient were able to back to her original condition. CONCLUSION: This was an intriguing case of IgAN flare-up following the first dose of mRNA-based COVID-19 vaccination.

A Population-Based Analysis of the Risk of Glomerular Disease Relapse after COVID-19 Vaccination.

BACKGROUND: Although case reports have described relapses of glomerular disease after COVID-19 vaccination, evidence of a true association is lacking. In this population-level analysis, we sought to determine relative and absolute risks of glomerular disease relapse after COVID-19 vaccination. METHODS: In this retrospective population-level cohort study, we used a centralized clinical and pathology registry (2000-2020) to identify 1105 adult patients in British Columbia, Canada, with biopsy-proven glomerular disease that was stable on December 14, 2020 (when COVID-19 vaccines first became available). The primary outcome was disease relapse, on the basis of changes in kidney function, proteinuria, or both. Vaccination was modeled as a 30-day time-varying exposure in extended Cox regression models, stratified on disease type. RESULTS: During 281 days of follow-up, 134 (12.1%) patients experienced a relapse. Although a first vaccine dose was not associated with relapse risk (hazard ratio [HR]=0.67; 95% confidence interval [95% CI], 0.33 to 1.36), exposure to a second or third dose was associated with a two-fold risk of relapse (HR=2.23; 95% CI, 1.06 to 4.71). The pattern of relative risk was similar across glomerular diseases. The absolute increase in 30-day relapse risk associated with a second or third vaccine dose varied from 1%-2% in ANCA-related glomerulonephritis, minimal change disease, membranous nephropathy, or FSGS to 3%-5% in IgA nephropathy or lupus nephritis. Among 24 patients experiencing a vaccine-associated relapse, 4 (17%) had a change in immunosuppression, and none required a biopsy. CONCLUSIONS: In a population-level cohort of patients with glomerular disease, a second or third dose of COVID-19 vaccine was associated with higher relative risk but low absolute increased risk of relapse.

Sibling cases of gross hematuria and newly diagnosed IgA nephropathy following SARS-CoV-2 vaccination.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has become a major part of the strategy to reduce Coronavirus disease 2019 (COVID-19) numbers worldwide. To date, vaccinations based on several mechanisms have been used clinically, although relapse of existent glomerulonephritis presenting as gross hematuria, and occurrence of de novo glomerulonephritis have been reported. CASE PRESENTATION: We report the first sibling cases newly diagnosed as immunoglobulin A (IgA) nephropathy after the second dose of SARS-CoV-2 vaccination. 15- and 18-year-old men presented with gross hematuria following the second dose of SARS-CoV-2 vaccine (Pfizer, BNT162b2) received on the same day. Pathological findings of each kidney biopsy specimen were consistent with IgA nephropathy. Gross hematuria in both cases spontaneously recovered within several days. CONCLUSIONS: These cases indicate that SARS-CoV-2 vaccination might trigger de novo IgA nephropathy or stimulate its relapse, and also highlight the necessity of understanding the immunological responses to the novel mRNA vaccines in patients with kidney diseases.

Newly-diagnosed immunoglobulin A nephropathy with increased plasma galactose-deficient-IgA1 antibody associated with mRNA COVID-19 vaccination: a case report.

Newly-diagnosed or relapses of immunoglobulin A nephropathy (IgAN) have been associated with COVID-19 vaccination in the literature. Most reported cases were mild clinical diseases characterized by microscopic haematuria and do not require dialysis treatment. This current case report describes a 55-year-old male patient that presented to the emergency department with acute kidney injury after receiving the first dose of the mRNA-1273 COVID-19 vaccine. After admission, his renal function deteriorated rapidly, and then he developed uraemic encephalopathy. He underwent emergency haemodialysis with a rapid improvement in his mental status. Renal biopsy showed newly-diagnosed IgA nephropathy along with markedly elevated plasma level of galactose-deficient-IgA1 (Gd-IgA1) antibody. The patient did not receive immunosuppressive treatment and is now dialysis-free. Immune activation is considered an essential factor in developing or exacerbating IgAN following COVID-19 vaccination. This current case report demonstrates that elevated Gd-IgA1 antibody may be the potential mechanistic link between COVID-19 vaccination and IgAN.

Epidemiological characteristics and pathological changes of primary glomerular diseases.

OBJECTIVE: By analyzing the pathological characteristics and clinical data of renal biopsy in our hospital in the past 20 years, to further understand the epidemic characteristics and pathological changes of primary glomerular disease, and to provide regional data for the big data of kidney disease in my country. METHODS: A retrospective analysis of 9448 patients with primary glomerular disease who were hospitalized in our hospital from January 1, 2000 to December 31, 2019, aged 18 years or older, and undergoing renal biopsy. Divided every 5 years into a group, a total of 4 groups (first group 2000.1.1-2004.12.31, second groups 2005.1.1-2009.12.31; third groups 2010.1.1-2014.12.31, fourth groups 2015.1.1-2019.12.31). RESULTS: ① There were more males than females, and male: female vs 1.53:1. The proportion of men in the past five years has increased compared with the previous 15 years. ② Mostly middle-aged, with a median age of 41.39 years old. The age is increasing over time. There are differences between the four groups, P <0.001; ③ The most common clinical manifestations are nephrotic syndrome, followed by chronic glomerulonephritis. Occult glomerulonephritis, the proportion of patients with nephrotic syndrome increases over time, first to fourth group (40.08%< 42.64% < 47.08%< 53.69%); ④ The most common pathology type from 2000 to 2009 was mesangial proliferative glomerulonephritis. IgA nephropathy was the most common type from 2010 to 2014, but the proportion of membranous nephropathy increased year by year, and it became the most common pathological type from 2015 to 2019; ⑤ The clinical and pathological manifestations of different genders are different, but there is no statistical difference. CONCLUSION: In the past 20 years, the primary glomerular disease is mainly middle-aged. There are more men than women. The most common type of clinical manifestation is nephrotic syndrome. The pathological type is mesangial proliferative glomerulonephritis. Over time, the average age is increasing, and the proportion of patients with renal syndrome is increasing. IgA nephropathy is the most common pathological type from 2010 to 2014, and membranous nephropathy has become the main pathological type in the past 5 years.

New-onset crescent IgA nephropathy following the CoronaVac vaccine: A case report.

RATIONALE: Although coronavirus disease 2019 (COVID-19) remains a global threat, administering effective and safe vaccines is currently the most promising strategy to curb the ongoing pandemic and decrease the number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. However, there remains some uncertainty regarding the safety of vaccines for patients with kidney disease. PATIENT CONCERNS: A 58-year-old man presented at our institution with gross hematuria 48 hours after receiving his first dose of the CoronaVac (Sinovac) vaccine. DIAGNOSES: Analysis of a renal biopsy sample led to the diagnosis of crescentic immunoglobulin A nephropathy (IgAN), which we considered an adverse event of receiving the CoronaVac vaccine in China. INTERVENTIONS: The patient's serum creatinine and albumin levels were 1.20 mg/dL and 31.3 g/L, respectively; as such, he was administered a diuretic. His serum creatinine level had risen to 7.45 mg/dL 1 month later, and he developed high blood pressure. The patient then received conventional doses of hormone therapy but developed recurrent fever, which led to the suspicion of active tuberculosis (which he had a history of) and suspension of the hormone therapy. OUTCOMES: The patient's renal function deteriorated further, and he ultimately underwent dialysis. LESSONS: The patient's course of events of apparent IgAN exacerbation should prompt nephrologists to closely follow patients with glomerular disease after they receive a COVID-19 vaccine, especially if persistent gross hematuria occurs.

An adolescent girl diagnosed with IgA nephropathy following the first dose of the COVID-19 vaccine.

There has been growing interest in reported cases of IgA nephropathy (IgAN) flare-up following administration of the coronavirus disease 2019 (COVID-19) vaccine. Our patient is a previously healthy 17-year-old girl who presented with a 10-year history of microscopic hematuria. Because there were no abnormal findings in blood examination or ultrasonography, we followed her up twice per year as asymptomatic hematuria. Although she never developed gross hematuria when she had upper respiratory infections or received an influenza vaccine, she presented with gross hematuria and proteinuria within a few days after receiving the first dose of the Pfizer vaccine. We performed renal biopsy 2 weeks after the first vaccination. It revealed minor glomerular abnormalities with diffuse mesangial IgA deposits, and we diagnosed her with mild IgAN. Gross hematuria was detected after both the first and second doses, although it changed to microscopic hematuria within 1 week. Additionally, her proteinuria resolved spontaneously approximately 10 days after the second dose of the vaccine. Therefore, we opted to observe her without administering medication. The causation between COVID-19 vaccination and IgAN flare-up remains unclear. Several reports showed IgAN patients presenting gross hematuria following the second dose of the Pfizer or Moderna vaccines. However, our patient developed gross hematuria and proteinuria even after the first dose and without known severe acute respiratory syndrome coronavirus 2 exposure. Nephrologists should inform both patients with IgAN and those with asymptomatic hematuria that this side effect can occur even after the first vaccination.

Gross hematuria can be an impact of severe acute respiratory syndrome coronavirus 2 vaccination on immunoglobulin A nephropathy: a case report.

BACKGROUND: Immunoglobulin A nephropathy is typically accelerated by upper respiratory tract infections and can relapse following vaccination. There have been reports of patients who presented with immunoglobulin A nephropathy flares with or without gross hematuria following coronavirus disease 2019 vaccination. However, this relationship remains to be elucidated. CASE PRESENTATION: Herein, we present the case of a patient with newly diagnosed immunoglobulin A nephropathy who presented with gross hematuria following the second dose of coronavirus disease 2019 vaccine. A 21-year-old Japanese woman presented with fever and new-onset gross hematuria 1 day after receiving the second dose of the coronavirus disease 2019 vaccine (Pfizer). She had microhematuria without proteinuria for 2 years at the time of her medical check-up. Gross hematuria resolved 6 days after the second dose of the coronavirus disease 2019 vaccine; however, microhematuria (> 100 per high-power field) and mild proteinuria were observed. She was admitted to our hospital 4 weeks after the second vaccination because of persistent urinary abnormalities. She was well before the vaccination and did not have any pulmonary involvement on chest radiography or any symptoms suggestive of coronavirus disease 2019. Renal biopsy revealed an immunoglobulin A nephropathy. The Oxford MEST-C score was M0E0S0T0C0. Our patient's urinary abnormalities implied exacerbation of immunoglobulin A nephropathy after coronavirus disease 2019 vaccination. CONCLUSIONS: In our case, gross hematuria served as a trigger for immunoglobulin A nephropathy diagnosis, suggesting that nephrologists should pay close attention to gross hematuria and urinalysis after coronavirus disease 2019 vaccination.