Clinical Profile and Outcomes of Patients with Membranous Nephropathy Resistant to Modified Ponticelli Regimen

Introduction: Membranous nephropathy is one of the most common causes of nephrotic syndrome. Among the available treatment options, the tried and tested regimen is the modified Ponticelli regimen. Despite adequate therapy, studies have shown that close to one-quarter of patients fail to attain complete remission. However, data is limited regarding patients who are resistant to this regimen. Method(s): This was an ambispective, observational study conducted in Madras Medical College, Chennai, India between April 2021 to August 2022. All patients with biopsy-proven primary membranous nephropathy resistant to modified Ponticelli regimen were included. Complete remission was defined as proteinuria < 0.5g/day combined with a stable eGFR. Partial remission was defined as reduction of proteinuria by 50% to < 3.5g/day but >0.5g/day. Resistance to therapy was defined as the failure to attain at least partial remission, 12 months after completion of modified Ponticelli regimen. Result(s): A total of 13 patients were enrolled in the study. The median age was 41 years (IQR 38-49) with a male preponderance (n=9;69%). Serum MPLA2R antibody was positive for 9 patients. All patients were negative for ANA and serology for hepatitis B, hepatitis C and HIV were negative. The most common clinical presentation was with nephrotic syndrome, seen in nine patients (69.23%). Renal failure was seen at presentation in 4 patients (30.76%), with one patient warranting initiation of hemodialysis. At 12 months, post completion of modified Ponticelli regimen, the median quantum of proteinuria was 8.7 grams per day. Due to trend towards normalisation of serum albumin and immunological remission, 3 patients were managed with optimised RAS inhibition after modified Ponticelli regimen. Currently, they are in partial remission. Four patients were treated with a second course of modified Ponticelli regimen. Of them one patient is in partial remission, while two patients had progressed to end-stage renal disease and are currently on maintenance hemodialysis. One patient who was resistant to the second course, was managed with a trial of calcineurin inhibitors (CNI) therapy followed by 4 doses of Rituximab (500mg each) due to persistent proteinuria. However, he was lost to follow up during the COVID pandemic and presented with end stage renal disease warranting hemodialysis. A trial of CNI therapy was given to 6 patients. All patients had nephrotic-range proteinuria 12 months post CNI therapy initiation. Five patients were then given Rituximab, among whom, two patients attained complete remission, while three patients have attained immunological and clinical remission. One patient was given a second trial of modified Ponticelli regimen following CNI therapy and is currently in complete remission. Two of these patients developed thrombotic complications - one patient diagnosed with coronary artery disease and one patient with renal vein thrombosis. Conclusion(s): Rituximab is a promising option for patients with primary membranous nephropathy who do not respond to modified Ponticelli regimen. No conflict of interestCopyright © 2023

Influenza A virus modulates ACE2 expression and SARS-CoV-2 infectivity in human cardiomyocytes.

Influenza A virus (IAV) and SARS-CoV-2 virus are both acute respiratory viruses currently circulating in the human population. This study aims to determine the impact of IAV infection on SARS-CoV-2 pathogenesis and cardiomyocyte function. Infection of human bronchial epithelial cells (HBEC), A549 cells, lung fibroblasts (HLF), monocyte derived macrophages (MDMs), cardiac fibroblasts (HCF) and hiPSC-derived cardiomyocytes with IAV enhanced the expression of ACE2, the SARS-CoV-2 receptor. Similarly, IAV infection increased levels of ACE2 in the lungs of mice and humans. Interestingly, we detected heavily glycosylated form of ACE2 in hiPSC-CMs and poorly glycosylated ACE2 in other cell types. Also, prior IAV infection enhances SARS-CoV-2 spike protein binding and viral entry in all cell types. However, efficient SARS-CoV-2 replication was uniquely inhibited in cardiomyocytes. Glycosylation of ACE2 correlated with enzymatic conversion of its substrate Ang II, induction of eNOS and nitric oxide production, may provide a potential mechanism for the restricted SARS-CoV-2 replication in cardiomyocytes.

COVID VACCINE ASSOCIATED GLOMERULAR DISEASES- A CASE SERIES

Introduction: Vaccination is a known trigger for the development of de-novo or flare of glomerular diseases. Here we present a case series of fourteen patients with COVID vaccine- associated glomerular diseases (CVAGD). Methods: Patients with new onset proteinuria, hematuria or renal failure after SARS- CoV2 vaccine were included in the study. Demographic and clinical details were collected and laboratory investigations including serum creatinine, albumin, urine microscopy and urine spot protein creatinine ratio were done. Renal biopsy specimens were subjected to light microscopy and immunofluorescence examination. Results: We cared for 14 patients with CVAGD. Of them, eight patients were males. The mean age was 25.7 years. Three patients had relapse of their previous disease while eleven patients had no previously detected renal diseases. Eleven patients had received COVISHIELD and three had received COVAXIN. All patients presented after the first vaccine dose. At presentation, seven patients had nephrotic syndrome, two patients had rapidly progressive renal failure and five patients had nephritic syndrome. The mean duration of symptom onset after vaccination was 18 days. Renal biopsy revealed IgA nephropathy in 3 patients, endocapillary proliferative glomerulonephritis in 2 patients, minimal change disease in 5 patients, pauci- immune glomerulonephritis (ANCA associated vasculitis) in one patient, lupus nephritis ISN/RPS class 3 in one and focal segmental glomerulosclerosis in two patients. There was no history of COVID infection in any of our patients. Three patients had renal failure at presentation but none required renal replacement therapy. The patients with MCD and FSGS were treated with steroids, patients with ANCA vasculitis and lupus nephritis were managed with the appropriate Cyclophosphamide and steroid regimens while the others were managed conservatively with anti-proteinuric medications. On follow up, five patients (One IgAN, three MCD, one endocapillary proliferative GN) achieved complete remission of proteinuria and resolution of renal failure, while the remaining eight patients achieved partial remission. One patient with MCD had a relapse of proteinuria 3 weeks after achieving partial remission, he responded well to steroid therapy. All 14 patients remain on close follow up. Conclusions: Although causality cannot be definitively established, there is a definite temporal association between the presentation of glomerular diseases and COVID vaccination, in the absence of other inciting factors. Hence, new-onset or relapse of glomerular diseases presenting post vaccination, although rare, should be observed as a possible adverse event. Intriguing questions such as how to proceed with the vaccination schedule in patients with CVAGD and would changing the vaccine type reduce the risk of relapse remain unanswered. No conflict of interest

Clinical characteristics and immunosuppression management in kidney transplant recipients infected with severe acute respiratory syndrome coronavirus 2 infection - An observational study

Background: COVID-19 infected kidney transplant patients need specialist care in tailoring their immunosuppression drugs alongside routine care. Methods and Materials: This is an observational data from a single center of 12 kidney transplant recipients (KTR) who were hospitalized with COVID-19 from April 2020 to November 2020. The demographics, COVID treatment including immunosuppressive drug regimen were reviewed. Their graft function during the stay, at the time of discharge, and 30 days after discharge was also reviewed. Results: Of 12 patients included, 83% were male patients. The median age was 37 years and the median time since transplant was 42 months. Common comorbidities were diabetes (50%), hypertension (50%), and cardiovascular disease (8%). Ninety-two percent had triple immunosuppressive regimen whereas 8% were in steroid-free protocol. Fifty percent had mild COVID, 8% had moderate disease, and 41% has severe COVID which was managed with institution-specified protocol. Steroids dose was increased in all patients. Antimetabolite was uniformly withdrawn in all patients irrespective of disease severity. Acute kidney injury was noted in 50% of patients which recovered to baseline at discharge. Graft function at 2 weeks and 30 days after discharge was stabilized close to their baseline value. Mortality was 8%. Conclusion: Reduction of immunosuppression, especially the withdrawal of antimetabolites, was found to be safe without graft rejection in KTRs.