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.

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.

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.

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.

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.

Aortic Stenosis and Aortic Valve Replacement among Patients with Chronic Kidney Disease: A Narrative Review.

BACKGROUND: Aortic stenosis (AS) can present with dyspnea, angina, syncope, and palpitations, and this presents a diagnostic challenge as chronic kidney disease (CKD) and other commonly found comorbid conditions may present similarly. While medical optimization is an important aspect in management, aortic valve replacement (AVR) by surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR) is the definitive treatment. Patients with concomitant CKD and AS require special consideration as it is known that CKD is associated with progression of AS and poor long-term outcomes. AIMS AND OBJECTIVES: The aim of the study was to summarize and review the current existing literature on patients with both CKD and AS regarding disease progression, dialysis methods, surgical intervention, and postoperative outcomes. CONCLUSION: The incidence of AS increases with age but has also been independently associated with CKD and furthermore with hemodialysis (HD). Regular dialysis with HD versus peritoneal dialysis (PD) and female gender have been associated with progression of AS. Management of AS is multidisciplinary and requires planning and interventions by the heart-kidney team to decrease the risk of further inducing kidney injury among high-risk population. Both TAVR and SAVR are effective interventions for patients with severe symptomatic AS, but TAVR has been associated with better short-term renal and cardiovascular outcomes. IMPLICATIONS FOR PRACTICE: Special consideration must be given to patients with both CKD and AS. The choice of whether to undergo HD versus PD among patients with CKD is multifactorial, but studies have shown benefit regarding AS progression among those who undergo PD. The choice regarding AVR approach is likewise the same. TAVR has been associated with decreased complications among CKD patients, but the decision is multifactorial and requires a comprehensive discussion with the heart-kidney team as many other factors play a role in the decision including preference, prognosis, and other risk factors.

Recent Developments in the Evaluation and Management of Cardiorenal Syndrome: A Comprehensive Review.

Cardiorenal syndrome (CRS) is an increasingly recognized diagnostic entity associated with high morbidity and mortality among acutely ill heart failure (HF) patients with acute and/ or chronic kidney diseases (CKD). While traditionally viewed as a state of decline in glomerular filtration rate (GFR) due to decreased renal perfusion, mainly due to therapeutic interventions to relieve congestive in HF, recent insights into the underlying pathophysiologic mechanisms of CRS led to a broader definition and further classification of CRS into 5 distinct types. In this comprehensive review, we discuss the classification of CRS, highlighting the underlying common pathogenetic pathways of heart failure and kidney injury, including increased congestion, neurohormonal dysregulation, oxidative stress as well as inflammation, and cytokine storm that are particularly evident in COVID-19 patients with multiorgan failure and also in those with other disorders including sepsis, systemic lupus erythematosus and amyloidosis. In this review we also present the recent advances in the diagnostic strategies of CRS including cardiac and renal biomarkers as well as advanced cardiac and renal imaging techniques that are available to aid in the diagnosis as well as in the prognostication of this disorder. Finally, we discuss the various therapeutic options available to-date, including fluid optimization, hemofiltration, renal replacement therapy as well as the role of SGLT2 inhibitors in light of recent data from RCTs. It is important to note that, CRS population are either excluded or underrepresented, at best, in major RCTs and therefore, therapeutic recommendations are largely extrapolated from HF and CKD clinical trials.

PICC line management among patients with chronic kidney disease.

More than 1 million peripherally inserted central catheters (PICC) are placed annually in the US and are used to provide convenient vascular access for a variety of reasons including long term antibiotic treatment, chemotherapy, parenteral nutrition, and blood draws. Although they are relatively easy to place and inexpensive, PICC line use is associated with many complications such as phlebitis/thrombophlebitis, venous thrombosis, catheter-related infection, wound infection, and central vein stenosis. These complications are far more deleterious for patients with chronic kidney disease (CKD) whose lives depend on a functioning hemodialysis access once they reach end stage kidney disease (ESKD). Despite recent guidelines to avoid PICC lines in CKD and ESKD patients, clinical use remains high. There is an ongoing urgency to educate and inform health care providers and the CKD patients themselves in preserving their venous real estate. In this article, we review AV access and PICC line background, complications associated with PICC lines in the CKD population, and recommendations for alternatives to placing a PICC line in this vulnerable patient population.

Lessons learnt and future directions in managing dialysis access during the COVID 19 pandemic: Patient and provider experience in the United States.

BACKGROUND: The COVID 19 pandemic adversely impacted delivery of preventive, routine, urgent, and essential care worldwide. Dialysis access care was particularly affected due to the lack of specific guidelines regarding procedures for its creation and maintenance. Early guidance by Centers for Medicare and Medicaid was inadvertently interpreted as guidance to stop dialysis access procedures. Prompt action by professional societies was needed to furnish detailed guidance to establish essential nature of these procedures. METHODS: The American Society of Diagnostic and Interventional Nephrology (ASDIN) issued a joint statement with Vascular Access Society of the Americas (VASA) - "Maintaining Lifelines for ESKD Patients" to clearly establish the role of vascular access as a lifeline for ESKD (End Stage Kidney Disease) patients and the importance and urgency of its timely management. ASDIN also conducted a survey in mid-2020, that was administered to the ASDIN database as well as shared with the general public via the organization's social media platforms. The respondents reported their experiences in the care of dialysis access, practice patterns and the utility of the ASDIN-VASA statement during the COVID 19 pandemic. RESULTS: Of the 2030 individual surveys sent, 581 were opened and 53 (9.1%) responses were received from different parts of the country and from different practice settings. ASDIN COVID 19 triage document was frequently utilized and 83% of respondents found the document valuable. The survey also revealed multiple obstacles, including logistical and financial issues that led to significant disruption of services. CONCLUSIONS: The care of dialysis access was significantly affected in the United States during the COVID 19 pandemic due to multiple reasons. ASDIN actions provided valuable specific guidance regarding and explored barriers to dialysis access care. We describe those results and discuss strategies to prevent COVID 19 transmission with innovative strategies of providing access care. Individualized decision making is of essence when considering dialysis access procedures.

Diabetic ketoacidosis.

Diabetic ketoacidosis (DKA) is a form of a hyperglycemic emergency mainly characterized by the triad of hyperglycemia, ketosis, and anion gap metabolic acidosis. DKA may be the initial presentation in approximately 25-40 % of patients with type 1 diabetes. It may also occur in at least 34% of patients with type 2 diabetes. DKA has economic as well as medical implications. This review aims to explore and discuss diabetic ketoacidosis, its pathophysiology, clinical presentation, diagnosis, and management, including nuances in special populations such as pediatrics, obstetrics, and patients with chronic kidney disease.

Diagnosis 101: diabetic kidney disease.

Chronic kidney disease (CKD) attributed to diabetes occurs in 20%-40% of patients with diabetes mellitus. Diabetic kidney disease (DKD) is recognized as the most common cause of end-stage kidney disease in the USA and most Western countries. For quite some time, it has been recognized that treatments based on inhibition of the renin-angiotensin system (RAS) can reduce the rates of cardiovascular morbidity and mortality in patients with DKD. Recently however, several novel agents, namely sodium-glucose co-transporter 2 inhibitors, dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 receptor agonists, were demonstrated to not only improve glycemic control but also to improve cardiovascular and renal outcomes. Another agent, a nonsteroidal mineralocorticoid antagonist, has also been shown to have cardiorenal benefits in patients with DKD. With such new developments, one would expect that it would eventually translate into further slowing CKD progression in the DKD population, provided that patients are diagnosed appropriately and in a timely manner. In this study, the authors attempt to investigate real-world data, looking at how well providers are establishing the diagnosis of DKD and its potential implications.

Clinical Efficacy, Safety, Tolerability, and Real-World Data of Patiromer for the Treatment of Hyperkalemia.

Hyperkalemia remains one of the most difficult consequences of disease state and treatment for patients with chronic kidney disease, heart failure, and diabetes. Controlling hyperkalemia can be difficult, but has become easier with the introduction of novel oral potassium binders. Patiromer was approved in 2015 for the treatment of hyperkalemia by the FDA in the United States. Several pivotal trials proved its efficacy, safety, and improved tolerability compared with previous hyperkalemia treatments. Additionally, many real-world publications and trials have given deeper insights into the capabilities of patiromer. We discuss improved disease state outcomes with combining patiromer with RAASi. This paper will also highlight new trials forthcoming that are highly anticipated to expand the possibilities in using patiromer to improve outcomes and populations.

Finerenone: a mineralocorticoid receptor antagonist for the treatment of chronic kidney disease associated with type 2 diabetes.

INTRODUCTION: Approximately 40% of people with type 2 diabetes (T2D) also have chronic kidney disease (CKD), which substantially increases their risk of cardiovascular (CV)-related complications and mortality. Until recently, no approved therapies have directly targeted inflammatory and fibrotic pathways that drive disease progression and organ damage in patients with CKD associated with T2D. AREAS COVERED: Finerenone is a potent, selective, nonsteroidal mineralocorticoid receptor antagonist (MRA) that targets fibrosis and inflammation by blocking overactivation of the MR in the kidneys and heart. Finerenone has been associated with significant reductions in kidney- and CV-related endpoints compared with placebo and minimal effects on serum potassium and kidney function in phase III trials involving >13,000 patients with diabetic kidney disease (DKD). In addition to reviewing the clinical data, this review compares the properties of finerenone with those of the older steroidal MRAs spironolactone and eplerenone. EXPERT OPINION: Unlike spironolactone and eplerenone, finerenone has demonstrated a favorable benefit-risk profile offering an effective new treatment for patients with CKD associated with T2D. Increases in serum potassium are predictable and manageable and should not discourage the use of finerenone in clinical practice. It is important to discuss where finerenone 'fits best' within the current DKD management landscape.