A Review of Focal Segmental Glomerulosclerosis Classification With a Focus on Genetic Associations.

Focal segmental glomerulosclerosis (FSGS) defines a distinct histologic pattern observed in kidney tissue that is linked to several distinct underlying causes, all converging on the common factor of podocyte injury. It presents a considerable challenge in terms of classification because of its varied underlying causes and the limited correlation between histopathology and clinical outcomes. Critically, precise nomenclature is key to describe and delineate the pathogenesis, subsequently guiding the selection of suitable and precision therapies. A proposed pathomechanism-based approach has been suggested for FSGS classification. This approach differentiates among primary, secondary, genetic, and undetermined causes, aiming to provide clarity. Genetic FSGS from monogenic mutations can emerge during childhood or adulthood, and it is advisable to conduct genetic testing in cases in which there is a family history of chronic kidney disease, nephrotic syndrome, or resistance to treatment. Genome-wide association studies have identified several genetic risk variants, such as those in apolipoprotein L1 (APOL1), that play a role in the development of FSGS. Currently, no specific treatments have been approved to treat genetic FSGS; however, interventions targeting underlying cofactor deficiencies have shown potential in some cases. Furthermore, encouraging results have emerged from a phase 2 trial investigating inaxaplin, a novel small molecule APOL1 channel inhibitor, in APOL1-associated FSGS.

An Updated Review of Membranous Nephropathy.

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. The discovery of phospholipase A2 receptor (PLA2R) as a target antigen has led to a paradigm shift in the understanding and management of MN. At present, serum PLA2R antibodies are used for diagnosis, prognostication, and guiding treatment. Now, with the discovery of more than 20 novel target antigens, antigen mapping is almost complete. The clinical association of certain antigens provides clues for clinicians, such as the association of nerve epidermal growth factor-like 1 with malignancies and indigenous medicines. Serum antibodies are detected for most target antigens, except exostosin 1 and 2 and transforming growth factor-beta receptor 3, but their clinical utility is yet to be defined. Genome-wide association studies and studies investigating environmental factors, such as air pollution, shed more light on the underpinnings of MN. The standard therapy of MN diversified from cyclical cyclophosphamide and steroids to include rituximab and calcineurin inhibitors over the past decades. Here, we provide a cutting-edge review of MN, focusing on genetics, immune system and environmental factors, novel target antigens and their clinical characteristics, and currently available and emerging novel therapies in MN.

Rituximab Resistance in Glomerular Diseases: A GlomCon Mini Review.

Resistance to rituximab B-cell depletion therapy is a clinically pertinent adverse sequela that can have significant implications for the treatment of immune-mediated glomerular diseases. The true incidence of rituximab resistance remains unknown; however, it is an increasingly recognized treatment complication. Resistance typically presents with suboptimal treatment response, rapid B-cell reconstitution, and a relapsing disease course. Although the diverse mechanisms resulting in rituximab resistance are ongoing topics of research, both primary and secondary mechanisms have been identified as key catalysts. The emergence of human antichimeric antibodies (HACAs) is a major cause of secondary resistance to rituximab therapy and typically appears following repeated drug exposure. Frequently, HACAs develop in the setting of underlying autoimmune disease and contribute to poor B-cell depletion, reduced rituximab therapeutic efficacy, and enhanced drug clearance. The clinical challenge of rituximab resistance necessitates heightened awareness among clinicians. Screening for HACAs should be considered in individuals with poor clinical response to rituximab, more rapid B-cell reconstitution, and relapsing disease. Detection of HACAs may guide treatment alterations, including addition of further immunosuppressive therapy and transitioning to a humanized B-cell depleting monoclonal antibody.

Kidney Biopsy in Management of Lupus Nephritis: A Case-Based Narrative Review.

Kidney involvement in patients with lupus highly increases morbidity and mortality. In recent years, several reports have emphasized the dissociation between clinical and histological findings and highlighted the role of kidney biopsy as an instrument for diagnosis and follow-up of lupus nephritis. The kidney biopsy at initial diagnosis allows an early diagnosis, assessment of activity and chronicity, and detection of nonimmune complex nephritis. A kidney biopsy repeated months after treatment aids in the detection of persistent histological inflammation, which has been linked to the occurrence of future kidney relapses. A kidney biopsy at a relapse detects histological changes including chronic scarring. Finally, a kidney biopsy in patients with a clinical response undergoing maintenance immunosuppression may aid therapy tapering and/or suspension. The evidence supporting the use of a kidney biopsy in different scenarios across the course of lupus nephritis is heterogeneous, with most reports assessing the value for the diagnosis of a first or relapsing flare. In contrast, less evidence suggests additional therapeutic-modifying information derived from repeat posttreatment biopsies and biopsies to evaluate treatment tapering or suspension. In this clinical case-based review, we examine the role of kidney biopsy as a tool to improve clinical outcomes of patients with lupus nephritis.

Approach to Pregnancy in Patients With Lupus Nephritis.

Active lupus nephritis (LN) in pregnancy is strongly associated with poor maternal and fetal outcomes and, therefore, has implications on the planning, timing, and management. Prepregnancy evaluation is essential for all LN patients with childbearing potential to ensure pregnancies proceed in a safe and timely manner. Both maternal and fetal risks are communicated to patient during the evaluation. Stratification into different risk profile groups is then made based on disease activity and organ impairment severity. Patients with LN are generally divided into 3 main groups. Patients with LN who become pregnant receive treatments that are nonteratogenic and optimal for fetal and maternal outcomes. Throughout the pregnancy period, these patients are monitored closely under surveillance by a multidisciplinary team of clinicians. The management of patients with LN in pregnancy can be challenging both diagnostically (distinguishing LN from pre-eclampsia and determining the role and timing of kidney biopsy) and therapeutically (LN flares during pregnancy and managing a newly diagnosed LN during pregnancy).

Novel Therapeutics for Management of Lupus Nephritis: What Is Next?

Lupus nephritis is a severe, organ-threatening manifestation of systemic lupus erythematosus. The current standard of care in the treatment of lupus nephritis is limited to broad-spectrum immunosuppressants, which have significant concerns of short- and long-term toxicity. With traditional approaches, kidney survival and patient outcomes have remained suboptimal. Robust research in the therapeutics of lupus nephritis has resulted in development of many novel drugs targeting specific inflammatory response pathways. Some newer agents have shown a definitive signal of benefit when added to standard of care. With the advent of precision medicine in nephrology, lupus nephritis treatment may undergo a shift toward incorporating approaches using these newer drugs and individualizing care of our patients. This review highlights major advances in management of lupus nephritis over the last 25 years and explores the ongoing trials of emerging therapies in lupus nephritis.

Successful Prolonged Desensitization to Epoetin-Alfa Hypersensitivity in an Adult Patient With Advanced Chronic Kidney Disease.

The use of erythropoiesis-stimulating agents (ESAs) reduces the need for recurrent blood transfusions in patients with advanced kidney disease. Rarely, allergic reactions to recombinant human erythropoietin can develop, complicating anemia management due to cross-reactivity between these agents. We report the use of an outpatient desensitization protocol, which was successfully completed in an adult patient who developed a maculopapular rash as a form of delayed-type hypersensitivity reaction (DTH) to epoetin-alfa (EPO) use, followed by successful re-introduction of EPO and continued tolerance.

Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors and CKD: Are You a #Flozinator?

Sodium/glucose cotransporter 2 (SGLT2) inhibitors have rapidly emerged as a novel therapy to reduce the rate of progression of chronic kidney disease (CKD). With humble beginnings in the 19th century for treating malaria, this class of drugs initially developed for the treatment of diabetes has now revolutionized the management of heart failure and CKD. SGLT2 inhibitors trigger glucosuria, thus modestly improving glycemic control. In addition, they have pleiotropic effects, such as reducing intraglomerular pressure and improving tubuloglomerular feedback, which lead to their beneficial effects on CKD progression. Recent data from randomized controlled trials have demonstrated the efficacy of this class of drugs in CKD. We briefly review the evidence from major trials on SGLT2 inhibitors in CKD, discuss the mechanisms of action and provide an overview of the safe and successful prescription of these medications.

Sodium-Glucose Cotransporter 2 Inhibitors and Urinary Tract Infection: Is There Room for Real Concern?

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have revolutionized our armamentarium for kidney and heart protection in patients with or without diabetes. Based on early reports of a limited number of cases, a concern for increased risk of urinary tract infections arose, which has become one of the main areas of concern for some clinicians. However, data from large randomized clinical trials and real-world population-based studies have not shown a significantly increased risk of UTI in patients on SGLT2 inhibitors. The goal of this brief review article is to review the literature and provide reassurance to patients and prescribers for the broader use of these agents.

GFR Estimation in Potential Living Kidney Donors: Race- and Nonrace-based Equations and Measured GFR.

Rationale & Objective: Recent studies evaluated and proposed new race-neutral, creatinine-based glomerular filtration rate (GFR) estimation equations. The performance of these equations in diverse potential living kidney donors requires study. Study Design: Cross-sectional study. Setting & Participants: 637 potential living kidney donors from one tertiary hospital with serum creatinine concentration measurement and GFR measurement by iohexol plasma clearance between October 2016 and December 2020. Exposure: Creatinine-based estimation of GFR by Chronic Kidney Disease Epidemiology Collaboration (2009, CKDEPI09; 2021, CKDEPI21) and Modification of Diet in Renal Disease equations with and without inclusion of race coefficient, where applicable. Outcomes: Equation bias, precision, accuracy, and accurate classification of GFR as equal to and above or below 80 mL/min/1.73 m2. Analytical Approach: GFR estimation equation performance compared to measured GFR (mGFR) by iohexol clearance. Results: The median bias of the CKDEPI21 equation underestimated mGFR by 2.8 mL/min/1.73 m2. The bias in the Black subgroup underestimated mGFR by 9.0 mL/min/1.73 m2. Compared to CKDEPI09 with and without race adjustment, the accuracy of CKDEPI21 increased across all subgroups. On average, 3.9% of individuals were misclassified by CKDEPI21 as having a GFR greater than, and 8.9% misclassified less than, 80 mL/min/1.73 m2, compared to 3.1% and 13.2% for CKDEPI09 with race adjustment, respectively. Total misclassification (either above or below 80 mL/min/1.73 m2) was 16.3% for CKDEPI21 and 16.0% for CKDEPI09 (with race adjustment). Limitations: Limited sample of individuals identifying as Black. Lack of cystatin C data. Conclusions: In our potential living donor sample, GFR estimation by creatinine-based CKDEPI21 is less biased and more accurate than previous creatinine-based estimated GFR equations. When evaluated by race, this summative improvement remains in individuals identifying as Asian, Hispanic, or White. More external validation is needed to assess whether the new equation is an improvement over the previous CKDEPI equation with a race coefficient.

Clinicopathologic Characteristics of JC Virus Nephropathy in Kidney Transplant Recipients.

BACKGROUND: The vast majority of polyomavirus nephropathy (PVN) is due to BK virus, but rare cases result from JC virus reactivation. To date, only a handful of biopsy-proven JC-PVN cases have been reported. Here, we describe the clinical and pathologic findings in 7 patients with biopsy-proven JC-PVN. METHODS: Search of the pathology archives at 2 institutions found 7 cases of JC-PVN. Clinical data were extracted from the electronic medical records, and the biopsies were reviewed. RESULTS: Four cases were diagnosed at 6 y posttransplant or later. The remaining 3 cases presented within approximately 2 y posttransplant, of which 2 showed subclinical JC-PVN on surveillance biopsy. Two early presenting patients were treated for acute rejection just before acquiring JC-PVN. Late presenting patients had higher chronicity, which correlated to worse outcome. All but 1 biopsy showed nonspecific inflammation within areas of interstitial fibrosis without significant inflammation in unscarred cortex. The earliest presenting patient was the exception and showed active inflammation with tubulitis. Viral cytopathic changes were detected in all cases with moderate or high-histologic viral load (pvl), showing preference for the distal tubules and medulla. The 2 cases with low pvl did not demonstrate cytopathic changes but were SV40 positive. CONCLUSIONS: JC-PVN can be insidious in presentation, which may cause delayed or missed diagnosis. Unlike BK-PVN, which typically occurs early in the posttransplant period, JC-PVN can occur both early and late following transplant. Overreliance on negative plasma and urine BK viral loads to exclude PVN can be a pitfall.