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Rationale: Vaccines remain central to the management of COVID-19 pandemic, including the need for repeat doses of vaccines to boost immunity. There has been an accumulating case count of glomerulopathies temporally associated with COVID-19 vaccination. This case series presents 4 patients who developed double-positive anti–glomerular basement membrane antibody (anti-GBM) and myeloperoxidase (MPO) antineutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis after COVID-19 mRNA vaccination. This report contributes to our collective knowledge about the pathophysiology and clinical outcomes associated with this rare complication. Presenting Concerns of the Patient: Four patients developed nephritic syndrome within 1 to 6 weeks after receiving a COVID-19 mRNA vaccine (3 post Pfizer-BioNTech and 1 post Moderna vaccination). Three of the 4 patients also had hemoptysis. Diagnosis: Three of the 4 patients had double-positive serology, whereas the fourth patient had renal biopsy findings consistent with double-positive disease, although anti-GBM serology was negative. All patients had renal biopsy findings consistent with double-positive anti-GBM and ANCA-associated glomerulonephritis. Interventions: All 4 patients were treated with pulse steroids, cyclophosphamide, and plasmapheresis. Outcomes: Of the 4 patients, 1 demonstrated complete remission, 2 remained dialysis-dependent, and the fourth is deceased. Of the 2 patients who received repeat vaccination with COVID-19 mRNA vaccine, 1 patient had second serologic flare of anti-GBM in response to the vaccine. Novel Findings: This case series reinforces growing evidence that COVID-19 mRNA vaccine-induced glomerulonephritis is a rare but real phenomenon. Dual ANCA and anti-GBM nephritis can present after the first dose of COVID-19 mRNA vaccine or after several administrations of the vaccine. We are the first to report cases of double-positive MPO ANCA and anti-GBM nephritis after Pfizer-BioNTech vaccination. To our knowledge, we are also the first to report outcomes of repeat COVID-19 vaccination in patients with de novo flare of ANCA and anti-GBM nephritis temporally associated with COVID-19 vaccination.

Rationale: Podocyte infolding glomerulopathy (PIG) is a newly described condition with only 37 cases reported worldwide. Due to its rarity, the pathogenesis and evolution of this disease is unclear. This case report contributes to our collective knowledge about the clinical and histological progression of this disease. Presenting concerns of the patient: Over the course of a year, a 52-year-old Malaysian woman with no known prior medical history developed progressively worsening edema and other findings consistent with nephrotic syndrome. Diagnosis: Unlike most patients with PIG, this patient did not have any autoimmune disease. She was Hepatitis B core antibody positive with a Hepatitis B surface antibody >1000, suggesting prior Hepatitis B infection with immunity. A renal biopsy was performed which was consistent with PIG. A second renal biopsy was done 2 years later which again showed characteristic findings of PIG with worsened podocyte effacement but no interval change in chronicity. Interventions: The patient was treated with blood pressure control and renin-angiotensin-aldosterone system (RAAS) blockade with irbesartan and spironolactone. She was also treated with prednisone at 1 mg/kg for 2 months followed by a taper for a total of 7 months of prednisone treatment. Outcomes: The patient had a partial response to a course of prednisone. However, since stopping steroids, her proteinuria and renal function has been gradually worsening. Teaching points: PIG is mostly found in patients of East Asian descent. It presents as proteinuria and is often associated with autoimmune disease but can be idiopathic. It is characterized on renal biopsy by infolding or protrusion of podocyte cytoplasm into glomerular basement membrane, as well as intramembranous cytoplasmic microspherules or microtubules. Atypical membranous nephropathy should be ruled out prior to diagnosis. Unlike membranous nephropathy, PIG usually responds at least partially to steroid monotherapy. To our knowledge, this is the first reported case of PIG from North America. Furthermore, it is the first case of PIG with repeat biopsy showing interval worsening of PIG rather than either resolution of PIG or transformation of PIG to a different diagnosis.

Familial hypobetalipoproteinemia (FHBL) is a rare genetic disorder of lipid metabolism that is associated with abnormally low serum levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B. It is an autosomal co-dominant disorder, and depending on zygosity, the clinical manifestations may vary from none to neurological, endocrine, hematological or liver dysfunction. Nonalcoholic fatty liver disease is common in persons with FHBL, however progression to nonalcoholic steatohepatitis is unusual. We describe here a patient with a novel APOB mutation, V703I, which appears to contribute to the severity of the FHBL phenotype. He had liver enzyme abnormalities, increased echogenicity of the liver consistent with steatosis, very low LDL cholesterol at 0.24 mmol/l (normal 1.8–3.5 mmol/l) and an extremely low apolipoprotein B level of 0.16 g/l (normal 0.6–1.2 g/l). APOB gene sequencing revealed him to be a compound heterozygote with two mutations (R463W and V703I). APOB R463W has previously been reported to cause FHBL. Genetic sequencing of his first-degree relatives identified the APOB V703I mutation in his normolipidemic brother and father and the APOB R463W mutation in his mother and sister, both of whom have very low LDL cholesterol levels. These results suggest that the APOB V703I mutation alone does not cause the FHBL phenotype. However, it is possible that it has a contributory role to a more aggressive phenotype in the presence of APOB R463W.

We recently reported that oxidized LDL (oxLDL) induces an oscillatory increase in intracellular calcium ([Ca2+]i) levels in macrophages. Furthermore, we have shown that these [Ca2+]i oscillations mediate oxLDL's ability to inhibit macrophage apoptosis in response to growth factor deprivation. However, the signal transduction pathways by which oxLDL induces [Ca2+]i oscillations have not been elucidated. In this study, we show that these oscillations are mediated in part by intracellular mechanisms, as depleting extracellular Ca2+ did not completely abolish the effect. Inhibiting sarco-endoplasmic reticulum ATPase (SERCA) completely blocked [Ca2+]i oscillations, suggesting a role for Ca2+ reuptake by the ER. The addition of oxLDL resulted in an almost immediate activation of sphingosine kinase (SK), which can increase sphingosine-1-phosphate (S1P) levels by phosphorylating sphingosine. Moreover, S1P was shown to be as effective as oxLDL in blocking macrophage apoptosis and producing [Ca2+]i oscillations. This suggests that the mechanism in which oxLDL generates [Ca2+]i oscillations may be 1) activation of SK, 2) SK-mediated increase in S1P levels, 3) S1P-mediated Ca2+ release from intracellular stores, and 4) SERCA-mediated Ca2+ reuptake back into the ER.

Oxidized LDL (oxLDL) promotes lipid accumulation as well as growth and survival signaling in macrophages. OxLDL uptake is mainly due to scavenger receptors SR-AI/II and CD36. However, other scavenger receptors such as lectin-like oxLDL receptor-1 (LOX-1) may also play a role. We used mice with targeted inactivation of the LOX-1 gene to define the role of this receptor in the uptake of oxLDL and in activation of survival pathways. There was no difference in uptake or degradation of 125I-oxLDL in unstimulated macrophages from wild-type and LOX-1 knockout mice and no difference in the rate of clearance of oxLDL from plasma in vivo. However, when expression of LOX-1 was induced with lysophosphatidylcholine, oxLDL uptake and degradation increased 2-fold in wild-type macrophages but did not change in LOX-1 knockout macrophages. Macrophages lacking LOX-1 showed the same stimulation of PKB phosphorylation and enhancement of survival by oxLDL as wild-type cells. These data show that LOX-1 does not alter the uptake of oxLDL in unstimulated macrophages and is not essential for the pro-survival effect of oxLDL in these cells. However, LOX-1 expression is highly inducible by lysophosphatidylcholine and pro-inflammatory cytokines, and if that occurred in macrophages within atheromas, LOX-1 could substantially increase oxLDL uptake by lesion macrophages.