Cardiovascular, Kidney Failure, and All-Cause Mortality Events in Patients with Focal Segmental Glomerulosclerosis in a U.S. Real-World Database.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) leads to proteinuria and progressive decline in glomerular filtration rate which correlates with kidney failure and increased cardiovascular risk. The purpose of this study was to estimate the effects of proteinuria on kidney failure status/all-cause mortality and cardiovascular disease events/all-cause mortality, as well as the relationship between progression to kidney failure and occurrence of cardiovascular disease/mortality events among adult patients (≥18 years old) with FSGS. METHODS: This was an observational, retrospective cohort study utilizing Optum® de-identified Market Clarity Data and proprietary Natural Language Processing (NLP) data. The study period was from January 1, 2007 through March 31, 2021, with patients in the overall cohort being identified from July 1, 2007 through March 31, 2021. The index date was the first FSGS ICD-10 diagnosis code or FSGS-related NLP term within the identification period. RESULTS: Elevated proteinuria >1.5 g/g and ≥3.5 g/g increased risk for kidney failure/all-cause mortality (adjusted hazard ratio [95% CI]: 2.34 [1.99-2.74] and 2.44 [2.09-2.84], respectively) and cardiovascular disease/all-cause mortality (adjusted hazard ratio [95% CI]: 2.11 [1.38-3.22] and 2.27 [1.44-3.58], respectively). Progression to kidney failure was also associated with a higher risk of cardiovascular disease/all-cause mortality (adjusted hazard ratio [95% CI]: 3.04 [2.66-3.48]. CONCLUSIONS: A significant proportion of FSGS patients experience kidney failure and cardiovascular disease events. Elevated proteinuria and progression to kidney failure were associated with a higher risk of cardiovascular disease/all-cause mortality events, and, elevated pre-kidney failure proteinuria was associated with progression to kidney failure/all-cause mortality events. Treatments that meaningfully reduce proteinuria and slow the decline in glomerular filtration rate have the potential to reduce the risk of cardiovascular disease, kidney failure and early mortality in patients with FSGS.

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.

Pitfalls of Current Diagnostic Criteria of Tumor Lysis Syndrome.

BACKGROUND: Tumor Lysis syndrome (TLS) is a well-recognized medical emergency in patients with cancer diagnosis. The diagnostic criteria of TLS have been revised many times since it was recognized, but still have many drawbacks limit diagnosis accuracy. SUMMARY: Autopsy studies in patients with perimortem diagnoses of TLS have shown that they may not have actually had TLS. Therefore, many cancer patients who are at risk for TLS, clinical and laboratory criteria may be fulfilled due to other causes of acute kidney injury. In this review, we aim to cast a spotlight on the shortcomings and pitfalls of the current diagnostic criteria for TLS, and propose a roadmap for developing a more rigorous criteria that improve on the diagnostic accuracy. KEY MESSAGES: Causes of AKI in patients with cancer other than TLS should be considered. Because current diagnostic criteria may miss those differential diagnosis, specific biomarkers that can tell when TLS is the underlying process is an important need, besides appropriate criteria that can jump over the pitfalls in the current criteria and enhance the recognition of TLS among other causes.

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.

Difelikefalin in Black/African American Hemodialysis Patients with Moderate-to-Severe Pruritus: Post-hoc Analysis of KALM-1 and KALM-2.

Black and African American (AA) people are over-represented in the kidney failure population; therefore, the safety and efficacy of difelikefalin in Black/AA patients was evaluated. This was a post hoc, pooled exploratory subgroup analysis of the Phase 3 KALM-1 and -2 studies. Patients undergoing hemodialysis (HD) who had moderate-to-severe chronic kidney disease-associated pruritus (CKD-aP) at enrollment were stratified into self-reported Black/AA or White subgroups. Patients were randomized (1:1) to receive intravenous (IV) difelikefalin 0.5 µg/kg or placebo for 12 weeks. Difelikefalin efficacy was assessed with validated patient-reported outcome questionnaires: 24-hour Worst Itch Numerical Rating Scale (WI-NRS), 5-D itch, and Skindex 10. There were 249 (29.3%) patients from the KALM studies that self-identified as Black/AA (n=135 difelikefalin; n=114 placebo). Clinically meaningful (≥3-point) reduction in WI-NRS score was achieved by 47.9% of Black/AA patients with difelikefalin versus 24.6% with placebo (P<0.001). More Black/AA patients achieved a ≥5-point 5-D itch total improvement (54.9% vs 35.7%; P=0.013) and a ≥15-point Skindex-10 score improvement with difelikefalin versus placebo (49.0% vs 28.9%; P=0.006) compared with White patients. Incidence of treatment-emergent adverse events (TEAEs) was higher for Black/AA patients (difelikefalin: 78.5%; placebo: 70.8%) versus White patients (difelikefalin: 64.8%; placebo: 61.8%). In this post hoc analysis, difelikefalin was efficacious in the Black/AA population and had an acceptable safety profile.

Impact of Difelikefalin on the Health-Related Quality of Life of Haemodialysis Patients with Moderate-To-Severe Chronic Kidney Disease-Associated Pruritus: A Single-Arm Intervention Trial.

OBJECTIVE: Chronic kidney disease-associated pruritus (CKD-aP) can have a substantial negative impact on health-related quality of life (HRQoL), including an increased risk of depression, anxiety and sleep disturbance. This trial aimed to assess the impact of intravenous difelikefalin on HRQoL in haemodialysis patients with moderate-to-severe CKD-aP. METHODS: Post hoc analysis of an open-label, multicentre, single-arm intervention trial assessed pruritus severity and HRQoL at baseline and at 12 weeks of difelikefalin treatment using Worst Itching Intensity Numerical Rating Scale (WI-NRS), Sleep Quality Numeric Rating Scale (SQ-NRS), 5-D itch scale, Skindex-10 scale, EQ-5D-5L with Pruritus Bolt-On (EQ-PSO). RESULTS: A total of 222 patients received ≥ 1 dose of difelikefalin, and 197 patients completed 12 weeks of difelikefalin treatment. Clinically meaningful changes from baseline to 12 weeks were observed in all disease-specific measures: 73.7% of patients achieved a ≥ 3-point reduction in the weekly mean of 24 h WI-NRS scores and 66% of patients experienced ≥ 3-point improvements in SQ-NRS scores. Improvements were also observed in all Skindex-10 scale and 5-D itch scale domain scores. The percentage of patients reporting no problems in all EQ-PSO domains increased from 1.4 to 24.7% (p < 0.001), respectively. Patients' generic HRQoL EQ-5D-5L mean utility and EQ-5D visual analogue scale scores increased from baseline to 12 weeks: mean changes 0.04 (p = 0.001) and 2.8 (p = 0.046), respectively. CONCLUSIONS: Patients undergoing haemodialysis with moderate-to-severe CKD-aP receiving difelikefalin reported experiencing clinically meaningful improvements in both their pruritus symptoms and itch-related QoL. CLINICALTRIALS: gov registration number, NCT03998163; first submitted, 7 May 2019.

Management of Hypertension in Diabetic Kidney Disease.

Hypertension is a critical component of cardiovascular disease progression in patients with chronic kidney disease, and specifically diabetic kidney disease (DKD). Causation versus correlation remains up for debate, but what has been confirmed is the delay of DKD progression when hypertension is controlled or moved to guideline drive ranges. Many medications have been studied and used in real world experience for best outcomes, and we discuss below the proven winners thus far making up the renin angiotensin aldosterone system. As well, we discuss guideline changing medications including sodium-glucose cotransporter 2 inhibitors and newer generation mineralocorticoid receptor antagonists. With the growing prevalence of diabetes and DKD in the population, newer agents are emerging in multiple drug class and will be highlighted below. Clinicians continue to search for the optimal care plans for this challenging patient population.

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.

Impact of Proteinuria and Kidney Function Decline on Health Care Costs and Resource Utilization in Adults With IgA Nephropathy in the United States: A Retrospective Analysis.

Rationale & Objective: Among patients with IgA nephropathy (IgAN), proteinuria and decline in kidney function may be associated with increased economic burden. This study aimed to provide current information on the epidemiology and economic burden of IgAN in the United States. Study Design: Retrospective cohort study. Setting & Study Population: Overall, 9,984 patients in the Optum's Market Clarity database identified by the presence of at least 2 natural language processing-derived IgAN signs and disease and symptoms terms; 813 with linked claims data included in a health care resource utilization/cost subcohort. Predictor: High-risk proteinuria (≥1 g/d), chronic kidney disease (CKD) stage. Outcomes: Standardized prevalence, health care resource utilization, costs. Analytical Approach: Descriptive statistics for categorical and continuous variables. Direct standardization for prevalence estimation. Generalized linear models for health care resource utilization/costs, reported as per-patient-per-month (PPPM) costs in 2020 US dollars. Results: The estimated standardized US prevalence of IgAN (2016-2020) was 329.0 per 1,000,000 persons. High-risk proteinuria (≥1 vs <1 g/d) was associated with a higher mean PPPM number of outpatient visits (3.49 vs 1.74; P = 0.01) and pharmacy claims (3.79 vs 2.41; P = 0.01), contributing to higher mean total costs PPPM ($3,732 vs $1,457; P = 0.01). Furthermore, higher CKD stage was also associated with higher health care resource utilization (number of outpatient visits PPPM, number of pharmacy claims PPPM, proportion of patients with inpatient visits and emergency department visits; P < 0.001) and mean total cost PPPM (from $2,111 CKD stage 1 to $10,703 CKD stage 5/kidney failure; P < 0.001). Limitations: Generalizability outside of the catchment group for the database, missing data/errors inherent in retrospective database studies, relatively small sample size, use of Optum Market Clarity standardized pricing algorithms, exclusion of out-of-pocket costs. Conclusions: Health care resource utilization and costs were higher for IgAN patients with high-risk proteinuria and worsening kidney function. Treatments that reduce proteinuria and slow CKD disease progression may reduce the economic burden associated with IgAN. Plain-Language Summary: Immunoglobulin A nephropathy (IgAN) is a rare kidney disease. Over time, the kidneys may leak protein into the urine (proteinuria). IgAN can lead to kidney failure. Because IgAN is rare, it is hard to know how many people have it. This study used electronic health records to estimate the number of patients with IgAN in the United States, describe the characteristics of patients, and understand their treatments and the costs. The number of patients with IgAN increased between 2016 and 2020. The researchers think this is because doctors learned more about IgAN. Patients with severe disease used more health care resources and had higher costs. The authors believe treatments that slow kidney damage may reduce the cost of treating IgAN.

Sex differences in cardiovascular outcomes of SGLT-2 inhibitors in heart failure randomized controlled trials: A systematic review and meta-analysis.

Background: In patients with heart failure (HF), randomized controlled trials (RCTs) of sodium-glucose transporter-2 inhibitors (SGLT-2is) have proven to be effective in decreasing the primary composite outcome of cardiovascular death and hospitalizations for HF. A recently published meta-analysis showed that the use of SGLT-2is among women with diabetes resulted in less reduction in primary composite outcomes compared with men. This study aims to explore potential sex differences in primary composite outcomes among patients with HF treated with SGLT-2is. Methods: We systematically searched the medical database from 2017 to 2022 and retrieved all the RCTs using SGLT-2is with specified cardiovascular outcomes. We used the PRISMA (Preferred Reporting Items for a Review and Meta-analysis) method to screen for eligibility. We evaluated the quality of studies using the Cochrane Risk of Bias tool. We pooled the hazard ratio (HR) of the primary composite outcomes in both sexes, performed a meta-analysis, and calculated the odds ratio (OR) of the primary composite outcomes based on sex. Results: We included 5 RCTs with a total number of 21,947 patients. Of these, 7837 (35.7 %) were females. Primary composite outcomes were significantly lower in males and females taking SGLT-2is compared to placebo (males - HR 0.77; 95 % CI 0.72 to 0.84; p = 0.00001; females - HR 0.75; 95 % CI 0.67 to 0.84; p = 0.00001). Pooled data from four of the RCTs (n = 20,725) revealed a greater occurrence of the primary composite outcomes in females compared with males (OR 1.32; 95 % CI 1.17 to 1.48; p = 0.0002). Conclusion: SGLT-2is reduce the risk of primary composite outcomes in patients with HF, regardless of sex; however, the benefits were less pronounced in women. Further research needs to be done to better explain these observed differences in outcomes.

Difelikefalin for the treatment of moderate-to-severe pruritus associated with chronic kidney disease on hemodialysis.

INTRODUCTION: Chronic kidney disease-associated pruritus (CKD-aP) is often experienced by patients with CKD receiving dialysis. Approximately 40% of hemodialysis patients are 'moderately' to 'extremely bothered' by itching, associated with reduced quality of life, poor sleep quality, and depression as well as worse clinical outcomes, including increased medication use, infections, hospitalizations, and mortality. AREAS COVERED: This review covers the pathophysiology and treatment landscape of CKD-aP, and the development, clinical efficacy, and safety profile of difelikefalin. We summarize the existing evidence, and discuss both the position of difelikefalin in the treatment pathway and potential future developments. EXPERT OPINION: Difelikefalin is a kappa opioid receptor agonist, with a primary mode of action that is outside of the central nervous system and provides an improved safety profile compared with other opioid agonists, with limited potential for abuse and dependency. Difelikefalin has demonstrated efficacy, tolerability, and safety profile in several large-scale clinical trials in more than 1,400 hemodialysis patients with CKD-aP treated for up to 64 weeks. Difelikefalin is the only approved treatment for CKD-aP in the U.S.A and Europe; other treatments are used off-label, have limited proof of efficacy in large-scale clinical trials in this patient population, and may present an increased risk of toxicity in patients with CKD.

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.

Empagliflozin in Adults with Chronic Kidney Disease (CKD): Current Evidence and Place in Therapy.

Chronic kidney disease guidelines and disease modifying therapy have seen a dramatic shift in the last 5 years. The SGLT2 inhibitor class of medications has been catapulted from hyperglycemia management medications, to cardiovascular and kidney disease improvement therapies. Multiple trials looking at dedicated cardiovascular and kidney endpoints have resulted in favorable results. This review will target empagliflozin and the exciting journey that it has taken along this path. Empagliflozin has been studied for hyperglycemia, cardiovascular, and kidney hard outcome endpoints. Both patients with diabetes and without have been rigorously studied and shown surprising results. The major implications for patients on empagliflozin will be shown. Future studies and directions are highly anticipated to add to the growing knowledge of the SGLT2 inhibitor class, as well as discover possibilities for new disease states to benefit from empagliflozin.

Transcatheter Aortic Valve Replacement-Associated Acute Kidney Injury: An Update.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a relatively novel minimally invasive procedure for the treatment of symptomatic patients with severe aortic stenosis. Although it has been proven effective in improving mortality and quality of life, TAVR is associated with serious complications, such as acute kidney injury (AKI). SUMMARY: TAVR-associated AKI is likely due to several factors such as sustained hypotension, transapical approach, volume of contrast use, and baseline low GFR. This narrative review aims to present an overview of the latest literature and evidence regarding the definition of TAVR-associated AKI, its risk factors, and its impact on morbidity and mortality. The review used a systematic search strategy with multiple health-focused databases (Medline, EMBASE) and identified 8 clinical trials and 27 observational studies concerning TAVR-associated AKI. Results showed that TAVR-associated AKI is linked to several modifiable and nonmodifiable risk factors and is associated with higher mortality. A variety of diagnostic imaging modalities have the potential to identify patients at high risk for development of TAVR-AKI; however, there are no existing consensus recommendations regarding their use as of this time. The implications of these findings highlight the importance of identifying high-risk patients for which preventive measures may play a crucial role, and should be maximized. KEY MESSAGE: This study reviews the current understanding of TAVR-associated AKI including its pathophysiology, risk factors, diagnostic modalities, and preventative management for patients.