Rationale and Design of a Phase 2, Double-blind, Placebo-Controlled, Randomized Trial Evaluating AMP Kinase-Activation by Metformin in Focal Segmental Glomerulosclerosis.

Introduction: Focal segmental glomerulosclerosis (FSGS), the most common primary glomerular disease leading to end-stage kidney disease (ESKD), is characterized by podocyte injury and depletion, whereas minimal change disease (MCD) has better outcomes despite podocyte injury. Identifying mechanisms capable of preventing podocytopenia during injury could transform FSGS to an "MCD-like" state. Preclinical data have reported conversion of an MCD-like injury to one with podocytopenia and FSGS by inhibition of AMP-kinase (AMPK) in podocytes. Conversely, in FSGS, AMPK-activation using metformin (MF) mitigated podocytopenia and azotemia. Observational studies also support beneficial effects of MF on proteinuria and chronic kidney disease (CKD) outcomes in diabetes. A randomized controlled trial (RCT) to test MF in podocyte injury with FSGS has not yet been conducted. Methods: We report the rationale and design of phase 2, double-blind, placebo-controlled RCT evaluating the efficacy and safety of MF as adjunctive therapy in FSGS. By randomizing 30 patients with biopsy-confirmed FSGS to MF or placebo (along with standard immunosuppression), we will study mechanistic biomarkers that correlate with podocyte injury or depletion and evaluate outcomes after 6 months. We specifically integrate novel urine, blood, and tissue markers as surrogates for FSGS progression along with unbiased profiling strategies. Results and Conclusion: Our phase 2 trial will provide insight into the potential efficacy and safety of MF as adjunctive therapy in FSGS-a crucial step to developing a larger phase 3 study. The mechanistic assays here will guide the design of other FSGS trials and contribute to understanding AMPK activation as a potential therapeutic target in FSGS. By repurposing an inexpensive agent, our results will have implications for FSGS treatment in resource-poor settings.

A Real-World Precision Medicine Program Including the KidneyIntelX Test Effectively Changes Management Decisions and Outcomes for Patients With Early-Stage Diabetic Kidney Disease.

INTRODUCTION/OBJECTIVE: The KidneyIntelX is a multiplex, bioprognostic, immunoassay consisting of 3 plasma biomarkers and clinical variables that uses machine learning to predict a patient's risk for a progressive decline in kidney function over 5 years. We report the 1-year pre- and post-test clinical impact on care management, eGFR slope, and A1C along with engagement of population health clinical pharmacists and patient coordinators to promote a program of sustainable kidney, metabolic, and cardiac health. METHODS: The KidneyIntelX in vitro prognostic test was previously validated for patients with type 2 diabetes and diabetic kidney disease (DKD) to predict kidney function decline within 5 years was introduced into the RWE study (NCT04802395) across the Health System as part of a population health chronic disease management program from [November 2020 to April 2023]. Pre- and post-test patients with a minimum of 12 months of follow-up post KidneyIntelX were assessed across all aspects of the program. RESULTS: A total of 5348 patients with DKD had a KidneyIntelX assay. The median age was 68 years old, 52% were female, 27% self-identified as Black, and 89% had hypertension. The median baseline eGFR was 62 ml/min/1.73 m2, urine albumin-creatinine ratio was 54 mg/g, and A1C was 7.3%. The KidneyIntelX risk level was low in 49%, intermediate in 40%, and high in 11% of cases. New prescriptions for SGLT2i, GLP-1 RA, or referral to a specialist were noted in 19%, 33%, and 43% among low-, intermediate-, and high-risk patients, respectively. The median A1C decreased from 8.2% pre-test to 7.5% post-test in the high-risk group (P < .001). UACR levels in the intermediate-risk patients with albuminuria were reduced by 20%, and in a subgroup treated with new scripts for SGLT2i, UACR levels were lowered by approximately 50%. The median eGFR slope improved from -7.08 ml/min/1.73 m2/year to -4.27 ml/min/1.73 m2/year in high-risk patients (P = .0003), -2.65 to -1.04 in intermediate risk, and -3.26 ml/min/1.73 m2/year to +0.45 ml/min/1.73 m2/year in patients with low-risk (P < .001). CONCLUSIONS: Deployment and risk stratification by KidneyIntelX was associated with an escalation in action taken to optimize cardio-kidney-metabolic health including medications and specialist referrals. Glycemic control and kidney function trajectories improved post-KidneyIntelX testing, with the greatest improvements observed in those scored as high-risk.

Real World Evidence and Clinical Utility of KidneyIntelX on Patients With Early-Stage Diabetic Kidney Disease: Interim Results on Decision Impact and Outcomes.

INTRODUCTION AND OBJECTIVE: The lack of precision to identify patients with early-stage diabetic kidney disease (DKD) at near-term risk for progressive decline in kidney function results in poor disease management often leading to kidney failure requiring unplanned dialysis. The KidneyIntelX is a multiplex, bioprognostic, immunoassay consisting of 3 plasma biomarkers and clinical variables that uses machine learning to generate a risk score for progressive decline in kidney function over 5-year in adults with early-stage DKD. Our objective was to assess the impact of KidneyIntelX on management and outcomes in a Health System in the real-world evidence (RWE) study. METHODS: KidneyIntelX was introduced into a large metropolitan Health System via a population health-defined approved care pathway for patients with stages 1 to 3 DKD between [November 2020 to March 2022]. Decision impact on visit frequency, medication management, specialist referral, and selected lab values was assessed. We performed an interim analysis in patients through 6-months post-test date to evaluate the impact of risk level with clinical decision-making and outcomes. RESULTS: A total of 1686 patients were enrolled in the RWE study and underwent KidneyIntelX testing and subsequent care pathway management. The median age was 68 years, 52% were female, 26% self-identified as Black, and 94% had hypertension. The median baseline eGFR was 59 ml/minute/1.73 m2, urine albumin-creatinine ratio was 69 mg/g, and HbA1c was 7.7%. After testing, a clinical encounter in the first month occurred in 13%, 43%, and 53% of low-risk, intermediate-risk, and high-risk patients, respectively and 46%, 61%, and 71% had at least 1 action taken within the first 6 months. High-risk patients were more likely to be placed on SGLT2 inhibitors (OR = 4.56; 95% CI 3.00-6.91 vs low-risk), and more likely to be referred to a specialist such as a nephrologist, endocrinologist, or dietician (OR = 2.49; 95% CI 1.53-4.01) compared to low-risk patients. CONCLUSIONS: The combination of KidneyIntelX, clinical guidelines and educational support resulted in changes in clinical management by clinicians. After testing, there was an increase in visit frequency, referrals for disease management, and introduction to guideline-recommended medications. These differed by risk category, indicating an impact of KidneyIntelX risk stratification on clinical care.

Home Dialysis: A Majority Chooses It, a Minority Gets It.

INTRODUCTION: When choosing a modality for outpatient renal replacement therapy, patients and medical providers have 3 options to choose from in-center hemodialysis (HD), home HD (HHD), and peritoneal dialysis (PD). In 2017, just over 10% of incident ESKD patients were on a home dialysis modality. We set out to determine outcomes of dialysis modality education in both pre-dialysis and dialysis patients. Moreover, we examined barriers that preclude patients from choosing home dialysis. METHODS: This was a single-center, retrospective study looking at patients who were referred to the CKD educator for dialysis modality education between January 1, 2019, and March 31, 2020. Patient demographics, preferred language of communication, stage of renal disease, and reasons for patients' refusal to undertake a home dialysis modality were recorded. Patients' average household income and driving distance to our home dialysis unit were calculated using their home zip code. RESULTS: 167 patients were referred for CKD education. Mean age was 60 years, and 59% male, 42% African American, 22% White, 7% Asian, and 28% were Hispanic or Latino. Only 23% of the total cohort chose in-center HD, while 74% chose a home dialysis modality (59% PD and 15% HHD), and the remaining patients remained undecided. 56% of in-center HD patients chose a home dialysis modality. The most commonly cited barriers to home dialysis were lack of a care partner, lack of home space, and patient preference. LIMITATIONS: Over 90% of our patients reside in NY City where home space is limited. We require in our home HD program that patients have a trained care partner present during their treatments. We cannot assume that all CKD stage-4 patients or higher were either referred for CKD education or followed through on the referral. CONCLUSIONS: A large discrepancy between informed patients' choices and the reality of the current dialysis landscape. Absence of a care partner, lack of home space, and patients not deemed appropriate surgical candidates were the main driving forces in their not opting for a home modality.

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.

Needle Migration to the Heart: An Unusual Association of Hemodialysis and Cardiovascular Morbidity.

In this report, we present a unique complication of hemodialysis: the hemodialysis access needle was lost into an arteriovenous fistula. The event went unnoticed for several months. The needle eventually migrated into the right ventricle, requiring an operative retrieval. Loss of the needle was likely unrecognized because of the use of a retracting safety cannula that conceals the needle within a sheath after removal. This case highlights a rare and potentially serious complication of hemodialysis access, demonstrates a possible hazard of retracting safety needles, and reviews the management of foreign bodies that have migrated into the heart.

Effect of cholecalciferol supplementation on inflammation and cellular alloimmunity in hemodialysis patients: data from a randomized controlled pilot trial.

BACKGROUND: Memory T-cells are mediators of transplant injury, and no therapy is known to prevent the development of cross-reactive memory alloimmunity. Activated vitamin D is immunomodulatory, and vitamin D deficiency, common in hemodialysis patients awaiting transplantation, is associated with a heightened alloimmune response. Thus, we tested the hypothesis that vitamin D3 supplementation would prevent alloreactive T-cell memory formation in vitamin D-deficient hemodialysis patients. METHODS AND FINDINGS: We performed a 12-month single-center pilot randomized, controlled trial of 50,000 IU/week of cholecalciferol (D3) versus no supplementation in 96 hemodialysis patients with serum 25(OH)D<25 ng/mL, measuring effects on serum 25(OH)D and phenotypic and functional properties of T-cells. Participants were randomized 2:1 to active treatment versus control. D3 supplementation increased serum 25(OH)D at 6 weeks (13.5 [11.2] ng/mL to 42.5 [18.5] ng/mL, p<0.001) and for the duration of the study. No episodes of sustained hypercalcemia occurred in either group. Results of IFNγ ELISPOT-based panel of reactive T-cell assays (PRT), quantifying alloreactive memory, demonstrated greater increases in the controls over 1 year compared to the treatment group (delta PRT in treatment 104.8+/-330.8 vs 252.9+/-431.3 in control), but these changes in PRT between groups did not reach statistical significance (p = 0.25). CONCLUSIONS: D3 supplements are safe, effective at treating vitamin D deficiency, and may prevent time-dependent increases in T-cell alloimmunity in hemodialysis patients, but their effects on alloimmunity need to be confirmed in larger studies. These findings support the routine supplementation of vitamin D-deficient transplant candidates on hemodialysis and highlight the need for large-scale prospective studies of vitamin D supplementation in transplant candidates and recipients. TRIAL REGISTRATION: Clinicaltrials.gov NCT01175798.

A prerotational, simulation-based workshop improves the safety of central venous catheter insertion: results of a successful internal medicine house staff training program.

BACKGROUND: The purpose of this study was to evaluate the effectiveness of a simulation-based workshop with ultrasonography instruction in reducing mechanical complications associated with central venous catheter (CVC) insertion. METHODS: A single-center prospective cohort study was conducted in the medical ICU and respiratory step-down unit of an urban teaching hospital. Fifty-six medical house staff members were trained prior to their rotations over a 6-month period. The data on mechanical complication rates after the implementation of the workshop were compared with previous experience when no structured educational program existed. RESULTS: There were 334 procedures in the preeducation period compared to 402 procedures in the posteducation period. The overall complication rate, including placement failure, in the preeducation and posteducation period was 32.9% and 22.9%, respectively (P < .01). Placement failure rate decreased from 22.8% to 16.2% (P = .02), and arterial punctures decreased from 4.2% to 1.5% (P = .03). Ultrasonography usage increased from 3.0% to 61.4% (P < .01). Multivariate analysis demonstrated that interns were more likely to cause overall mechanical complications compared with fellows and attending physicians in the preeducation period (P = .02); however, this trend was not observed in the posteducation period. Catheter site and ultrasonography usage significantly affected the overall complication rate in both periods, and ultrasound-guided femoral CVC was the safest procedure in the posteducation period. CONCLUSIONS: Implementation of a prerotational workshop significantly improved the safety of CVC insertion, especially for CVCs placed by inexperienced operators. We suggest that simulation-based training with ultrasonography instruction should be conducted if house staff members are responsible for CVC placement.

Relationship between proteinuria and venous thromboembolism.

Nephrotic syndrome is known to cause venous thromboembolism (VTE) due to urine loss of antithrombin III and activation of the coagulation system. We hypothesized that the degree of proteinuria may predict the development of VTE. This was a retrospective case-controlled study of in-patients urban academic teaching hospital from April, 2007 to March, 2009 and who had undergone an imaging study for VTE. All radiology reports (N = 1,647) for CT angiography of chest and Doppler sonogram of extremities were reviewed. The following data were collected: race/ethnicity, degree of proteinuria on urinalysis, serum protein and albumin levels, risk factors for VTE and renal function. The study population consisted of 284 patients with VTE and 280 age/sex matched controls. Relative to those who did not have proteinuria, patients who tested positive for protein had a 3.4-fold increased risk of VTE (odds ratio (OR) 3.4, 95% confidence interval [2.4, 5.0]). The association was unchanged when adjusted for other risk factors. Patients with proteinuria may have an increased risk of venous thromboembolism.