KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases

KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases.

Primary membranous nephropathy (MN) is an autoimmune disease mainly caused by autoantibodies against the recently discovered podocyte antigens: the M-type phospholipase A2 receptor 1 (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A). Assays for quantitative assessment of anti-PLA2R antibodies are commercially available, but a semiquantitative test to detect anti-THSD7A antibodies has been only recently developed. The presence or absence of anti-PLA2R and anti-THSD7A antibodies adds important information to clinical and immunopathologic data in discriminating between primary and secondary MN. Levels of anti-PLA2R antibodies and possibly, anti-THSD7A antibodies tightly correlate with disease activity. Low baseline and decreasing anti-PLA2R antibody levels strongly predict spontaneous remission, thus favoring conservative therapy. Conversely, high baseline or increasing anti-PLA2R antibody levels associate with nephrotic syndrome and progressive loss of kidney function, thereby encouraging prompt initiation of immunosuppressive therapy. Serum anti-PLA2R antibody profiles reliably predict response to therapy, and levels at completion of therapy may forecast long-term outcome. Re-emergence of or increase in antibody titers precedes a clinical relapse. Persistence or reappearance of anti-PLA2R antibodies after kidney transplant predicts development of recurrent disease. We propose that an individualized serology-based approach to MN, used to complement and refine the traditional proteinuria-driven approach, will improve the outcome in this disease.

A Proposal for a Serology-Based Approach to Membranous Nephropathy

https://www.ajkd.org/article/S0272-6386(16)00700-9/pdf

Membranous Nephropathy: A Journey From Bench to Bedside

By definition, viral-associated GN indicates the direct pathogenic relationship between active viral replication and the development of acute GN. This definition is in sharp contrast to the semantic label and pathophysiologic foundation behind postinfectious GN that uniquely develops only during a period of resolved and absent active infection. The primary example of postinfectious GN are the glomerular lesions described after a pharyngeal or cutaneous streptococcal infection and do not represent the clinical or immunologic pattern seen with viral-associated GN. Hepatitis B (HBV) is the most common chronic viral infection in the world affecting >400 million people which is more than double the prevalence of chronic HIV and hepatitis C carriers combined. In addition, 10%-20% of HBV patients may be coinfected with hepatitis C and 5%-10% will have coinfection with HIV. Being able to distinguish the different types of GN seen with each viral infection is essential for the practicing clinician as each virus requires its own specific antiviral therapy. HBV-induced immune complex disease with renal injury lies on one end of the spectrum of disorders that occurs after a prolonged chronic carrier state. On the opposite end of the spectrum are renal diseases that develop from acute or subacute viral infections. One important glomerular lesion in this category is the association of collapsing FSGS with acute active cytomegalovirus, Epstein-Barr virus, and parvovirus B19 infection. The data supporting or disproving this relationship for each of these viruses will be discussed. A second renal manifestation of acute viral infections often occurs with many different sporadic or epidemic infections such as dengue and hantavirus and can lead to a transient proliferative GN that resolves upon viral clearance. The complex interplay of HBV and all viruses with the immune system provides conceptual lessons on the pathophysiology of immune complex GN that can be applied to all infection-related renal disease and plays an integral role in developing an approach to therapeutic intervention.

Viral-Associated GN: Hepatitis B and Other Viral Infections

Objective: This study examined the expression of renal phospholipase A2 receptor (PLA2R) in idiopathic and secondary membranous nephropathy (MN) Methods: Patients with biopsy-proven MN and non-MN were enrolled Renal PLA2R was examined using an anti-PLA2R antibody (anti-PLA2R-Ab), and circulating PLA2R-Ab was detected by indirect immunofluorescence Results: Renal PLA2R was detected along the capillary loop in 84% patients with idiopathic MN but not in those with any other primary glomerulonephritis Only 1 of 38 patients with class V lupus nephritis showed renal PLA2R positive In hepatitis B virus-associated MN (HBV-MN), 64% showed renal PLA2R positive, and PLA2R overlapped with HBsAg along the capillary loop In addition, renal PLA2R positivity was closely associated with serum PLA2R-Ab Renal PLA2R positive was present in all the patients with serum PLA2R-Ab positive and in 53% of patients with serum PLA2R-Ab negative However, in patients with renal PLA2R negative, serum PLA2R-Ab was all negative Conclusion: Renal biopsy PLA2R positivity was common in idiopathic MN and HBV-MN but rare in lupus-associated MN, and it was closely associated with serum PLA2R-Ab production Further studies examining the association between PLA2R and HBV-MN may shed light on the mechanism of idiopathic MN or HBV-MN

Renal Phospholipase A2 Receptor in Hepatitis B Virus-Associated Membranous Nephropathy

Background:
According to the renal phospholipase A2 receptor (PLA2R) immunohistochemistry, idiopathic membranous nephropathy (iMN) could be categorized into PLA2R-associated and non-PLA2R-associated iMN. This study aimed to examine whether the non-PLA2R-associated iMN had any difference in clinical features compared with PLA2R-associated iMN.


Methods:
A total of 231 adult patients diagnosed as iMN were recruited to this retrospective study. Renal PLA2R expression was examined by immunofluorescence. Among these patients, 186 (80.5%) with complete baseline clinical data were used for further study. Urinary protein excretion, serum albumin, and creatinine were analyzed. For those patients with follow-up longer than 1 year, the relationship between PLA2R and response to immunosuppressants were analyzed. The t-test was used for parametric analysis and the Mann-Whitney U-test was used for nonparametric analysis. Categorical variables were described as frequencies or percentages, and the data were analyzed with Pearson’s Chi-square test or Fisher’s exact test.


Results:
Of the 231 iMN patients, 189 showed renal detectable PLA2R expression (81.8%). The baseline serum creatinine, serum albumin, and urine protein excretion were not significantly different between PLA2R-associated (n = 145) and non-PLA2R-associated iMN patients (n = 41). However, about 1/3 of the non-PLA2R-associated iMN had abnormal serological tests, significantly more common than PLA2R-associated iMN (31.7% vs. 8.3%, P= 0.000). The non-PLA2R-associated iMN had lower C4 levels compared with PLA2R-associated iMN (P = 0.004). The non-PLA2R-associated iMN patients also showed a better response to immunosuppressants (complete remission [CR] 42.9%; partial remission [PR] 14.3%) compared with PLA2R-associated iMN (CR 3.2%; PR 48.4%, P = 0.004) at the 3rd month.


Conclusions:
There were no significant differences in serum creatinine, albumin, and urine protein excretion between PLA2R-associated and non-PLA2R-associated iMN, while the non-PLA2R-associated iMN patients showed more abnormal serological tests. The non-PLA2R-associated iMN seemed to respond more quickly to the immunosuppressive therapy compared with PLA2R-associated iMN.


Key words: 
Immunosuppressive Therapy; Membranous Nephropathy; Phospholipase A2 Receptor; Serology

Renal Phospholipase A2 Receptor and the Clinical Features of Idiopathic Membranous Nephropathy.

Background and objective Around 33.5 million patients suffered from atrial fibrillation (AF), causing complications and increasing mortality and disability rate. Upstream treatment for AF is getting more popular in clinical practice in recent years. The angiotensin receptor-neprilysin inhibitor (ARNI) is one of the potential treatment options. Our study aimed to investigate the effect of ARNI on atrial electrical instability and structural remodeling in AF. Methods Our research consisted of two parts – a retrospective real-world clinical study and an animal experiment on calmness to verify the retrospective founding. In the retrospective study, we reviewed all patients (n = 110) who had undergone the first AF ablation from 1 August 2018 to 1 March 2022. Patients with ARNI (n = 36) or angiotensin II receptor antagonist (ARB) (n = 35) treatment were enrolled. Their clinical data, ultrasound cardiogram (UCG) and Holter parameters were collected before radiofrequency catheter ablation (RFCA) as baseline and at 24-week follow-up. Univariate and multivariate logistic regression analysis were performed. In the animal experiment, we established an AF model (n = 18) on canines by rapid atrial pacing. After the successful procedure of pacing, all the 15 alive beagles were equally and randomly assigned to three groups (n = 5 each): Control group, ARB group, and ARNI group. UCG was performed before the pacing as baseline. Physiological biopsy, UCG, and electrophysiological study (EPS) were performed at 8-week. Results Clinical data showed that the atrial arrhythmia rate at 24-week was significantly lower in ARNI group compared to ARB group (P < 0.01), and ARNI was independently associated with a lower atrial arrhythmia rate (P < 0.05) at 24-week in multivariate regression logistic analysis. In the animal experiment, ARNI group had a higher atrial electrical stability score and a shorter AF duration in the EPS compared to Control and ARB group (P < 0.05). In the left atrium voltage mapping, ARNI group showed less low voltage and disordered zone compared to Control and ARB group. Compared to Control group, right atrium diameter (RAD), left ventricle end-diastolic volume index (LVEDVI), E/A, and E/E′ were lower in ARNI group (P < 0.05) at the 8-weeks follow-up, while left atrium ejection fraction (LAEF) and left ventricle ejection fraction (LVEF) were higher (P < 0.01). Compared to ARB group, LVEF was higher in ARNI group at the 8-week follow-up (P < 0.05). ARB and ARNI group had a lower ratio of fibrotic lesions in the left atrium tissues compared to Control group (P < 0.01), but no difference was found between the ARB and the ARNI group. Conclusion ARNI could reduce atrial electrical instability in AF in comparison with ARB in both retrospective study and animal experiment.

/pdf/effect-of-angiotensin-receptor-neprilysin-inhibitor-on-181wmr0y.pdf

Effect of angiotensin receptor-neprilysin inhibitor on atrial electrical instability in atrial fibrillation

The decreasing characteristic size of transistors leads to a large increase in the Soft Error Rate of circuits. In view of the Single Event Transient generated by the combined circuit, this paper proposes a Triple Modular Redundancy structure Flip-Flop with filtering function to replace the standard Flip-Flop, and the Flip-Flop to be replaced is divided according to the soft error sensitivity. At the same time, aiming at the problem of automatic equalization of various indicators of the generated circuit in the replacement process, this paper explores an optimization architecture based on the "BP-NSGA-III" algorithm, which can automatically determine the position, number and radiation level of the Flip-Flop to be replaced in the circuit, and achieve the comprehensive optimization of the three design indicators of radiation hardening performance, area and power consumption.

Research on anti single event transient multi-objective optimization technology based on sensitive flip-flop replacement

In this paper, Single event transient (SET) shielding is reinforced by reinforcing the Flip-flop (FF), and the FF is preprocessed according to the path timing and soft error (SER) sensitivity. At the same time, aiming at the problem of automatic balancing of various indicators of the circuit generated during the replacement process, an optimization architecture based on the “BP NSGA-III” algorithm is explored. Based on the optimization theory research, without sacrificing the circuit performance, the overhead of area and power consumption are within the acceptable range, the final soft error rate is reduced by about 66.09%, and the radiation hardening ability is greatly improved.

Research on multi-objective optimization of radiation hardened integrated circuits based on “BP NSGA-III” optimization architecture

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