Membranoproliferative Glomerulonephritis Pattern of Injury.

Membranoproliferative glomerulonephritis (MPGN) is no longer a disease but a pattern of injury in various diseases. Characterized by electron-dense deposits, mesangial proliferation, and duplication of the glomerular basement membrane, MPGN was previously classified by findings seen by electron microscopy. However, recognizing complement dysfunction in relation to cases with the MPGN pattern of injury substantially changed our view of its pathogenesis. A new classification, including immune complex-mediated and complement-mediated MPGN, has become preferable and has been adopted by international guidelines. Despite these advancements, accurate diagnosis of MPGN remains a clinical challenge, given the pathological and clinical similarities between immune complex-mediated and complement-mediated MPGN. Additional testing, such as molecular and genetic testing, is often necessary. Here, we will summarize our current understanding of the MPGN pattern of injury from a pathology perspective as an introductory article in the following chapters.

IgA Nephropathy After SARS-CoV-2 Vaccination.

Here we present the first case of newly diagnosed IgA nephropathy (IgAN) after a SARS-CoV-2 vaccination. A 30-year-old man with no known past medical history presented with gross hematuria and subnephrotic proteinuria 24 hours after the second dose of the mRNA-1273 SARS-CoV-2 vaccine. A kidney biopsy showed IgAN. He was started on an angiotensin receptor blocker, resulting in proteinuria reduction. Similar to natural infection of SARS-CoV-2, persons who receive 2 mRNA-based vaccines demonstrate robust antibodies against the receptor-binding domain (RBD) of the S1 protein. Given the uniqueness of glycosylation of RBD and potent stimulation of immune response from mRNA-based vaccine compared to other vaccines, we hypothesize that our patient developed de novo antibodies, leading to IgA-containing immune-complex deposits. This case highlights the urgency of understanding the immunological responses to novel mRNA-based SARS-CoV-2 vaccines in more diverse populations. Despite the lack of clear causality, nephrologists should be alerted if any new-onset hematuria or proteinuria is observed.

Molecular Analysis of the Kidney From a Patient With COVID-19-Associated Collapsing Glomerulopathy.

Recent case reports suggest that coronavirus disease 2019 (COVID-19) is associated with collapsing glomerulopathy in African Americans with apolipoprotein L1 gene (APOL1) risk alleles; however, it is unclear whether disease pathogenesis is similar to HIV-associated nephropathy. RNA sequencing analysis of a kidney biopsy specimen from a patient with COVID-19-associated collapsing glomerulopathy and APOL1 risk alleles (G1/G1) revealed similar levels of APOL1 and angiotensin-converting enzyme 2 (ACE2) messenger RNA transcripts as compared with 12 control kidney samples downloaded from the GTEx (Genotype-Tissue Expression) Portal. Whole-genome sequencing of the COVID-19-associated collapsing glomerulopathy kidney sample identified 4 indel gene variants, 3 of which are of unknown significance with respect to chronic kidney disease and/or focal segmental glomerulosclerosis. Molecular profiling of the kidney demonstrated activation of COVID-19-associated cell injury pathways such as inflammation and coagulation. Evidence for direct severe acute respiratory syndrome coronavirus 2 infection of kidney cells was lacking, which is consistent with the findings of several recent studies. Interestingly, immunostaining of kidney biopsy sections revealed increased expression of phospho-STAT3 (signal transducer and activator of transcription 3) in both COVID-19-associated collapsing glomerulopathy and HIV-associated nephropathy as compared with control kidney tissue. Importantly, interleukin 6-induced activation of STAT3 may be a targetable mechanism driving COVID-19-associated acute kidney injury.

Acute Kidney Injury in Hospitalized Patients with COVID-19.

IMPORTANCE: Preliminary reports indicate that acute kidney injury (AKI) is common in coronavirus disease (COVID)-19 patients and is associated with worse outcomes. AKI in hospitalized COVID-19 patients in the United States is not well-described. OBJECTIVE: To provide information about frequency, outcomes and recovery associated with AKI and dialysis in hospitalized COVID-19 patients. DESIGN: Observational, retrospective study. SETTING: Admitted to hospital between February 27 and April 15, 2020. PARTICIPANTS: Patients aged ≥18 years with laboratory confirmed COVID-19 Exposures: AKI (peak serum creatinine increase of 0.3 mg/dL or 50% above baseline). Main Outcomes and Measures: Frequency of AKI and dialysis requirement, AKI recovery, and adjusted odds ratios (aOR) with mortality. We also trained and tested a machine learning model for predicting dialysis requirement with independent validation. RESULTS: A total of 3,235 hospitalized patients were diagnosed with COVID-19. AKI occurred in 1406 (46%) patients overall and 280 (20%) with AKI required renal replacement therapy. The incidence of AKI (admission plus new cases) in patients admitted to the intensive care unit was 68% (553 of 815). In the entire cohort, the proportion with stages 1, 2, and 3 AKI were 35%, 20%, 45%, respectively. In those needing intensive care, the respective proportions were 20%, 17%, 63%, and 34% received acute renal replacement therapy. Independent predictors of severe AKI were chronic kidney disease, systolic blood pressure, and potassium at baseline. In-hospital mortality in patients with AKI was 41% overall and 52% in intensive care. The aOR for mortality associated with AKI was 9.6 (95% CI 7.4-12.3) overall and 20.9 (95% CI 11.7-37.3) in patients receiving intensive care. 56% of patients with AKI who were discharged alive recovered kidney function back to baseline. The area under the curve (AUC) for the machine learned predictive model using baseline features for dialysis requirement was 0.79 in a validation test. CONCLUSIONS AND RELEVANCE: AKI is common in patients hospitalized with COVID-19, associated with worse mortality, and the majority of patients that survive do not recover kidney function. A machine-learned model using admission features had good performance for dialysis prediction and could be used for resource allocation.

Removal of gadolinium by dialysis: review of different strategies and techniques.

Nephrogenic systemic fibrosis (NSF) has been related to the administration of gadolinium-based contrast agents for magnetic resonance imaging studies in patients with kidney disease. After reviewing the pathophysiology of NSF, we discuss the possible factors contributing to the toxicity of gadolinium in susceptible patients, including the excessive amounts of intravenous iron and erythropoietin as well as the inflammatory states commonly seen in patients treated with hemodialysis. Since free gadolinium is the most accepted risk factor for NSF, we provide some suggestions to improve clearance of both free and chelated gadolinium using different dialysis strategies and techniques. J. Magn. Reson. Imaging 2009;30:1347-1349. (c) 2009 Wiley-Liss, Inc.

Rituximab treatment of fibrillary glomerulonephritis.

Fibrillary glomerulonephritis belongs to a group of disorders characterized by pathogenic deposition of fibrils in glomeruli. This glomerulopathy tends to progress to end-stage kidney disease, and there currently are no treatments of proven benefit, including corticosteroids and cytotoxic agents. Because the glomerular deposits contain an immunoglobulin component, it was postulated that anti-B-cell therapy with rituximab, an anti-CD20 monoclonal antibody, may be effective in the treatment of patients with fibrillary glomerulonephritis. We describe 3 patients with fibrillary glomerulonephritis who were treated with rituximab for nephrotic-range proteinuria. Each patient also received standard antiproteinuria therapy, including blockade of the renin-angiotensin system and strict blood pressure control. All patients showed a decrease in proteinuria to less than 1.5 g/d of protein by 27 months, and kidney function was preserved throughout the duration of therapy and follow-up. No adverse effects were seen with rituximab. These outcomes suggest that treatment with rituximab may be a promising approach to the management of fibrillary glomerulonephritis, an entity previously considered refractory to therapy.

Therapy for Proliferative Lupus Nephritis.

Proliferative lupus nephritis requires prompt diagnosis and treatment with immunosuppressive therapy. Cyclophosphamide is the longest studied agent, but mycophenolate mofetil has recently emerged as an efficacious induction and maintenance treatment that does not impart the risk of infertility. However, overall remission rates remain suboptimal and there is a need for improved therapeutic options. To this end, ongoing clinical studies are focusing on agents that target key molecules and pathways implicated in the pathogenesis of lupus nephritis based on previous animal and human studies. This article reviews key findings of trials supporting established induction and maintenance treatment regimens along with novel therapeutic investigations.

Bortezomib for Reduction of Proteinuria in IgA Nephropathy.

INTRODUCTION: IgA nephropathy is the most common glomerulonephritis in the world. We conducted a pilot trial (NCT01103778) to test the effect of bortezomib in patients with IgA nephropathy and significant proteinuria. METHODS: We treated 8 consecutive subjects from July 2011 until March 2016 with 4 doses of bortezomib. All subjects had biopsy-proven IgA nephropathy and proteinuria of greater than 1 g per day. They were given 4 doses of bortezomib i.v. at 1.3 mg/m2 of body surface area per dose. Changes in proteinuria and renal function were followed for 1 year after enrollment. The primary endpoint was full remission defined as proteinuria of less than 300 mg per day. RESULTS: All 8 subjects received and tolerated 4 doses of bortezomib over a 2-week period during enrollment. The median baseline daily proteinuria was 2.46 g (interquartile range: 2.29-3.16 g). At 1-year follow-up, 3 subjects (38%) had achieved the primary endpoint. The 3 subjects who had complete remission had Oxford classification T scores of 0 before enrollment. Of the remaining 5 subjects, 1 was lost to follow-up within 1 month of enrollment and 4 (50%) did not have any response or had progression of disease. CONCLUSION: Proteasome inhibition by bortezomib may reduce significant proteinuria in select cases of IgA nephropathy. Subjects who responded to bortezomib had Oxford classification T score of 0 and normal renal function.

Bortezomib therapy for nephrotic syndrome due to idiopathic membranous nephropathy.

Idiopathic membranous nephropathy is a common cause of nephrotic syndrome in adults. The nephrotic syndrome due to idiopathic membranous nephropathy is often resistant to glucocorticosteroids and requires an alkylating agent such as chlorambucil or cyclophosphamide to induce remission. Recent studies illustrate that antibodies against the autoantigen M-type phospholipase A2 receptor contribute to a vast majority but not all cases of idiopathic membranous nephropathy. Herein, we report a patient with nephrotic syndrome due to membranous nephropathy that was resistant to 6 months of therapy with ramipril and high-dose glucocorticosteroids but responded to a single cycle of bortezomib infusion.