Validation of a novel smartphone application-enabled, patient-operated skin barrier device.

BACKGROUND: Transepidermal water loss (TEWL) and surface capacitance measure skin barrier permeability and stratum corneum (SC) hydration, respectively, and are frequently utilized in atopic dermatitis clinical trials. Many barrier devices are costly and often used only in the academic setting. GPSkin is a low-cost, patient-operated device that measures both TEWL and SC hydration. This study aimed to test the reliability of GPSkin and assess its correlation with current industry standards. MATERIALS AND METHODS: GPSkin was compared to the Biox AquaFlux (TEWL) and Courage-Khazaka Corneometer (SC hydration). Participants with healthy skin (n = 50) collected measurements with GPSkin in Trial 1 without any device education and in Trial 2 with additional instruction. In Trial 2, the investigator also performed measurements with GPSkin. Spearman's coefficients (rs ) were performed to assess device correlation. Intraclass correlation coefficients (ICC) were calculated to determine reliability. RESULTS: Overall, GPSkin was moderately correlated with current industry device measurements for TEWL (Trial 1 rs :0.48; Trial 2 rs :0.40 participant, 0.34 investigator) and SC hydration (Trial 1 rs :0.63; Trial 2 rs :0.45). GPSkin demonstrated "good" test-retest reliability for both TEWL (ICC: 0.89) and SC hydration (ICC: 0.85) measurements when participants were provided with some device education. There was no difference in reliability between participants provided with device education and investigators. CONCLUSION: Based on these findings, we concluded that GPSkin provides reasonably precise and reliable measurements of SC hydration and TEWL as compared to current devices.

Is it Important to Prevent and Treat Protein-Energy Wasting in Chronic Kidney Disease and Chronic Dialysis Patients?

Protein-energy wasting (PEW), which essentially refers to decreased body protein mass and fuel (energy) reserves, is common in advanced chronic kidney disease (CKD) patients and end-stage kidney disease patients undergoing chronic dialysis. The term PEW is used rather than protein-energy malnutrition because many causes of PEW in CKD and end-stage kidney disease patients does not involve reduced nutrient intake (e.g., catabolic illness, oxidants, biologicals lost in urine and dialysate, acidemia). The prevalence of PEW in CKD increases as glomerular filtration rate declines and is highest in chronic dialysis patients. PEW in CKD is important because it is associated with substantially increased morbidity and mortality and reduced quality of life. Many signs of PEW can be improved with nutritional therapy. It is not known whether amelioration or eradication of PEW by treatment of underlying illnesses, nutritional therapy, and/or other measures will reduce morbidity and mortality or improve quality of life. Clinical trials are indicated to answer these questions.

Is There a Role for Diaphoresis Therapy for Advanced Chronic Kidney Disease Patients?

Diaphoresis therapy to remove water and solutes for the treatment of advanced chronic kidney disease (CKD) and chronic dialysis patients is an inadequately characterized treatment that was first reported over 50 years ago. Intensive diaphoresis, induced by heat treatment with saunas (dry heat) or hot baths (wet heat), can substantially increase cutaneous losses of water, urea, sodium, potassium, chloride, lactate, and possibly other solutes. How effectively diaphoresis therapy might remove many uremic toxins is not known. Diaphoresis therapy is not sufficiently effective to replace dialysis treatments, but theoretically it might be used to delay the start of chronic dialysis, supplement infrequent dialysis therapy, or augment chronic dialysis treatment perhaps especially for dialysis patients with excessive salt and water intake. Diaphoresis might be helpful for managing edema resistant states. Because it is inexpensive, diaphoresis may be particularly valuable in lower income countries where some patients may need to pay for dialysis. Diaphoresis might enhance some aspects of dietary treatment. The short-term and long-term effectiveness, safety, and patient acceptance of diaphoretic therapy need to be more carefully investigated.

North American experience with Low protein diet for Non-dialysis-dependent chronic kidney disease.

Whereas in many parts of the world a low protein diet (LPD, 0.6-0.8 g/kg/day) is routinely prescribed for the management of patients with non-dialysis-dependent chronic kidney disease (CKD), this practice is infrequent in North America. The historical underpinnings related to LPD in the USA including the non-conclusive results of the Modification of Diet in Renal Disease Study may have played a role. Overall trends to initiate dialysis earlier in the course of CKD in the US allowed less time for LPD prescription. The usual dietary intake in the US includes high dietary protein content, which is in sharp contradistinction to that of a LPD. The fear of engendering or worsening protein-energy wasting may be an important handicap as suggested by a pilot survey of US nephrologists; nevertheless, there is also potential interest and enthusiasm in gaining further insight regarding LPD's utility in both research and in practice. Racial/ethnic disparities in the US and patients' adherence are additional challenges. Adherence should be monitored by well-trained dietitians by means of both dietary assessment techniques and 24-h urine collections to estimate dietary protein intake using urinary urea nitrogen (UUN). While keto-analogues are not currently available in the USA, there are other oral nutritional supplements for the provision of high-biologic-value proteins along with dietary energy intake of 30-35 Cal/kg/day available. Different treatment strategies related to dietary intake may help circumvent the protein- energy wasting apprehension and offer novel conservative approaches for CKD management in North America.

Is there a role for ketoacid supplements in the management of CKD?

Ketoacid (KA) analogues of essential amino acids (EAAs) provide several potential advantages for people with advanced chronic kidney disease (CKD). Because KAs lack the amino group bound to the α carbon of an amino acid, they can be converted to their respective amino acids without providing additional nitrogen. It has been well established that a diet with 0.3 to 0.4 g of protein per kilogram per day that is supplemented with KAs and EAAs reduces the generation of potentially toxic metabolic products, as well as the burden of potassium, phosphorus, and possibly sodium, while still providing calcium. These KA/EAA-supplemented very-low-protein diets (VLPDs) can maintain good nutrition, but the appropriate dose of the KA/EAA supplement has not been established. Thus, a KA/EAA dose-response study for good nutrition clearly is needed. Similarly, the composition of the KA/EAA supplement needs to be reexamined; for example, some KA/EAA preparations contain neither the EAA phenylalanine nor its analogue. Indications concerning when to inaugurate a KA/EAA-supplemented VLPD therapy also are unclear. Evidence strongly suggests that these diets can delay the need for maintenance dialysis therapy, but whether they slow the loss of glomerular filtration rate in patients with CKD is less clear, particularly in this era of more vigorous blood pressure control and use of angiotensin/aldosterone blockade. Some clinicians prescribe KA/EAA supplements for patients with CKD or treated with maintenance dialysis, but with diets that have much higher protein levels than the VLPDs in which these supplements have been studied. More research is needed to examine the effectiveness of KA/EAA supplements with higher protein intakes.

Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing.

BACKGROUND: Tumoral calcinosis is an autosomal recessive disorder characterized by ectopic calcification and hyperphosphatemia. METHODS: We describe a family with tumoral calcinosis requiring amputations. The predominant metabolic anomaly identified in three affected family members was hyperphosphatemia. Biochemical and phenotypic analysis of 13 kindred members, together with exome analysis of 6 members, was performed. RESULTS: We identified a novel Q67K mutation in fibroblast growth factor 23 (FGF23), segregating with a null (deletion) allele on the other FGF23 homologue in three affected members. Affected siblings had high circulating plasma C-terminal FGF23 levels, but undetectable intact FGF23 or N-terminal FGF23, leading to loss of FGF23 function. CONCLUSIONS: This suggests that in human, as in experimental models, severe prolonged hyperphosphatemia may be sufficient to produce bone differentiation proteins in vascular cells, and vascular calcification severe enough to require amputation. Genetic modifiers may contribute to the phenotypic variation within and between families.

Risk-Tailoring Radiotherapy for Endometrial Cancer: A Narrative Review.

Endometrial cancer is the most common gynecologic cancer in the United States and it contributes to the second most gynecologic cancer-related deaths. With upfront surgery, the specific characteristics of both the patient and tumor allow for risk-tailored treatment algorithms including adjuvant radiotherapy and systemic therapy. In this narrative review, we discuss the current radiation treatment paradigm for endometrial cancer with an emphasis on various radiotherapy modalities, techniques, and dosing regimens. We then elaborate on how to tailor radiotherapy treatment courses in combination with other cancer-directed treatments, including chemotherapy and immunotherapy. In conclusion, this review summarizes ongoing research that aims to further individualize radiotherapy regimens for individuals in an attempt to improve patient outcomes.

Associations Between Race and Survival Outcomes Among Veterans With Head and Neck Cancer in a Racially Diverse Setting.

Objective: There is limited data on the impact of clinical-demographic factors on survival outcomes among veterans with head and neck squamous cell carcinoma (HNSCC). This study was undertaken to evaluate the impact of race and other factors on overall survival (OS) in a population of veterans with HNSCC treated with curative intent. Methods: Demographic and clinical data were collected on veterans with HNSCC treated with curative intent at our institution between 1999 and 2021. The primary outcome was 3-year OS. Secondary outcomes included treatment delay intervals, including time to treatment initiation (TTI), total package time, and duration of chemoradiation (DCRT). Results: Of 260 veterans with HNSCC, black veterans had significantly lower 3-year OS (49.4%) compared to white veterans (65%, P = .019). Black veterans were also more likely to experience delays in treatment initiation (median TTI 46 vs 41 days; P = .047). Black patients were more likely to receive radiation alone (25.8% [black] vs 8.4% [white]; P < .001) and less likely to receive adjuvant therapy if treated surgically (11.1% [black] vs 22.4% [white]; P = .004), despite any statistically significant difference in stage of their tumor at presentation (Stage I: 21.2% [black] vs 19.6% [white]; P = .372); (Stage IV: 44.4% [black] vs 48.6% [white]; P = .487). Other factors associated with worse 3-year OS included older age (P = .023), lower body mass index (P = .026), neurocognitive disorder/dementia (P = .037), mental health disorders (P = .020), hypopharyngeal primary (P = .001), higher stage disease (P = .002), treatment type (P = .001), need for prophylactic gastrostomy tube (P = .048) or tracheotomy (P = .005), recurrent disease (P = .036), persistent disease (P < .001), distant metastases (P = .002), longer TTI (P = .0362), and longer DCRT (P = .004). Discussion: Black race appears to be an independent predictor of 3-year OS in veterans with HNSCC. Further studies are warranted to determine the factors responsible for disparities in survival. Implications for Practice: This study evaluated the ways in which race affects survival for US veterans with head and neck cancer. The authors found that black veterans had an increased risk of death compared to white patients, and also experienced delays when receiving treatment. Level of Evidence: Level IV.

No independent association of serum phosphorus with risk for death or progression to end-stage renal disease in a large screen for chronic kidney disease.

Whether higher serum phosphorus levels are associated with a higher risk for death and/or progression of chronic kidney disease (CKD) is not well established, and whether the association is confounded by access and barriers to care is unknown. To answer these questions, data of 10,672 individuals identified to have CKD (estimated glomerular filtration rate <60 ml/min per 1.73 m(2)) from those participating in a community-based screening program were analyzed. Over a median follow-up of 2.3 years, there was no association between quartiles of serum phosphorus and all-cause mortality (adjusted hazards ratio for serum phosphorus over 3.3 to 3.7, over 3.7 to 4.1, and over 4.1 mg/dl, respectively: 1.22 (0.95-1.56), 1.00 (0.76-1.32), and 1.00 (0.75-1.33); reference, serum phosphorus of 3.3 mg/dl and below). Individuals in the highest quartile for serum phosphorus had a significantly higher risk for progression to end-stage renal disease (ESRD) (unadjusted hazards ratio, 6.72 (4.16-10.85)); however, the risk became nonsignificant on adjustment for potential confounders. There was no appreciable change in hazards ratio with inclusion of variables related to access and barriers to care. Additional analyses in subgroups based on 12 different variables yielded similar negative associations. Thus, in the largest cohort of individuals with early-stage CKD to date, we could not validate an independent association of serum phosphorus with risk for death or progression to ESRD.

Searching for new care models for chronic kidney disease.

Chronic kidney disease is associated with increased death risk. The estimated size of this high-risk population is too large for effective care to be delivered by nephrologists alone and will require models of care delivery that include partnerships with primary-care physicians and incorporate physician extenders. Studies show that some of these care models provide outcomes similar to those seen with nephrologists as sole providers; whether they are cost-effective or improve satisfaction with care remains to be demonstrated.

Age and the associations of living donor and expanded criteria donor kidneys with kidney transplant outcomes.

BACKGROUND: Recent studies show a survival advantage with kidney transplant in elderly patients compared with those on dialysis therapy. STUDY DESIGN: In our present study, we examined and compared the association of expanded criteria donor (ECD) kidney and living kidney donation with the outcome of kidney transplant across different ages, including elderly recipients. SETTING & PARTICIPANTS: Using the Scientific Registry of Transplant Recipients, we identified 145,470 adult kidney transplant patients. Mortality and death-censored transplant failure risks were estimated by Cox proportional regression analyses during follow-up with a median of 3.9 years. PREDICTORS: ECD kidney and living kidney donation and age compared with others. OUTCOMES: Mortality and death-censored transplant failure risk. RESULTS: Patients were aged 45 ± 16 years and included 40% women and 19% patients with diabetes. Compared with transplant recipients 55 to younger than 65 years, the fully adjusted death-censored transplant failure risk was higher in patients 75 years and older (HR, 1.30; 95% CI, 1.09-1.56), 35 to younger than 55 years (HR, 1.13; 95% CI, 1.08-1.17), and 18 to younger than 35 years (HR, 1.64; 95% CI, 1.57-1.71). Compared with non-ECD kidneys, ECD kidneys were significant predictors of mortality in nonelderly patients (18-<35 years: HR, 1.46 [95% CI, 1.19-1.77]; 35-<55 years: HR, 1.23 [95% CI, 1.14-1.32]; and 55-<65 years: HR, 1.26 [95% CI, 1.15-1.38]) and patients 65 to younger than 70 years (HR, 1.20; 95% CI, 1.05-1.36), but not in other groups of elderly patients (HRs of 1.12 [95% CI, 0.93-1.36] for 70-<75 years and 1.04 [95% CI, 0.74-1.47] for ≥75 years). Similar results were found for risk of transplant loss. Compared with deceased donor kidneys, a living donor kidney was associated with better survival in all age groups and lower transplant loss risk in patients younger than 70 years. LIMITATIONS: Unmeasured confounders cannot be adjusted for. CONCLUSIONS: For deceased donors, ECD kidneys are not associated with increased mortality or transplant failure in recipients older than 70 years. For all types of donors, the persistent association between living donor kidneys and lower all-cause mortality across all ages suggests that, if possible, elderly patients gain longevity from living donor kidney transplant.

Associations between access to care and awareness of CKD.

BACKGROUND: Most individuals with chronic kidney disease (CKD) in the United States are unaware of their condition, creating challenges in implementing early interventions to delay disease progression. Whether characteristics expected to enhance health care access are associated with greater CKD awareness has not been studied adequately. METHOD: Data from volunteer participants in the National Kidney Foundation's Kidney Early Evaluation Program (KEEP), 2000-2010, with presumed CKD (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m(2) or albumin-creatinine ratio >30 mg/g) were analyzed. Given that the diagnosis of CKD was based on a single measurement of kidney function, the diagnosis is presumed, but not confirmed. Associations of CKD awareness with measures of access to care (health insurance coverage, type of health insurance, prescription drug coverage, and self-reported level of difficulty obtaining care) were examined using logistic regression. RESULTS: Of 29,144 participants with CKD, 6,751 (23%) reported CKD awareness. No significant association was found between availability of health insurance or prescription drug coverage and CKD awareness; results did not vary by diabetic status or in analyses restricted to participants with eGFR <60 mL/min/1.73 m(2). Participants reporting extreme or some difficulty obtaining medical care were more likely than those reporting no difficulty to be aware of CKD (adjusted OR, 1.25; 95% CI, 1.05-1.50). CONCLUSIONS: Most KEEP participants with CKD are unaware of the condition, results that are not modified by the availability of health insurance or prescription drug coverage. The mechanisms underlying the association of perceived difficulty in access to care with greater CKD awareness require further study.

Hemoglobin level and survival in hemodialysis patients with polycystic kidney disease and the role of administered erythropoietin.

Interventional trials indicate adverse outcomes when hemoglobin >13 g/dL is targeted in patients with chronic kidney disease (CKD) who receive erythropoiesis-stimulating agents (ESAs). It is not clear whether high-achieved hemoglobin with minimal to no ESA administration as observed in some patients with polycystic kidney disease (PKD) is also associated with poor outcomes. Survival models were examined to assess the association between hemoglobin increments and mortality in a 6-year cohort of 2,402 PKD and 110,875 non-PKD hemodialysis patients across infrequent versus frequent ESA therapy defined as ESA < 25% of cohort time versus otherwise, respectively. Mortality risk was estimated by Cox proportional regression [hazard ratio (HR) and 95% of confidence interval] analysis. Patients with PKD were aged 58 ± 13 years and included 46% women 14% Blacks, respectively. Fully adjusted death HRs of time-averaged hemoglobin increments <11.0, 12.0 to <13.0 g/dL (reference: 11.0 to <12.0 g/dL) for frequent ESA therapy were 2.57 (1.48-4.48), 0.60 (0.43-0.82), and 0.81 (0.50-1.29), whereas for infrequent ESA therapy they were 1.33 (0.47-3.78), 0.28 (0.13-0.61), and 0.22 (0.09-0.57), respectively. Hence, in patients with PKD who require infrequent ESA, incrementally higher achieved hemoglobin including > 13.0 g/dL exhibits better survival; this incremental survival gain of higher hemoglobin is not observed in patients with PKD receiving frequent ESA administration, in whom hemoglobin concentration > 13 exhibits increased mortality.

Improving pediatric multiple sclerosis interventional phase III study design: a meta-analysis.

Background: To support innovative trial designs in a regulatory setting for pediatric-onset multiple sclerosis (MS), the study aimed to perform a systematic literature review and meta-analysis of relapse rates with interferon ß (IFN ß), fingolimod, and natalizumab and thereby demonstrate potential benefits of Bayesian and non-inferiority designs in this population. Methods: We conducted a literature search in MEDLINE and EMBASE from inception until 17 June 2020 of all studies reporting annualized relapse rates (ARR) in IFN ß-, fingolimod-, or natalizumab-treated patients with pediatric-onset relapsing-remitting MS. These interventions were chosen because the literature was mainly available for these treatments, and they are currently used for the treatment of pediatric MS. Two researchers independently extracted data and assessed study quality using the Cochrane Effective Practice and Organization of Care - Quality Assessment Tool. The meta-analysis estimates were obtained by Bayesian random effects model. Data were summarized as ARR point estimates and 95% credible intervals. Results: We found 19 articles, including 2 randomized controlled trials. The baseline ARR reported was between 1.4 and 3.7. The meta-analysis-based ARR was significantly higher in IFN ß-treated patients (0.69, 95% credible interval: 0.51-0.91) versus fingolimod (0.11, 0.04-0.27) and natalizumab (0.17, 0.09-0.31). Based on the meta-analysis results, an appropriate non-inferiority margin versus fingolimod could be in the range of 2.29-2.67 and for natalizumab 1.72-2.29 on the ARR ratio scale. A Bayesian design, which uses historical information for a fingolimod or natalizumab control arm, could reduce the sample size of a new trial by 18 or 14 patients, respectively. Conclusion: This meta-analysis provides evidence that relapse rates are considerably higher with IFNs versus fingolimod or natalizumab. The results support the use of innovative Bayesian or non-inferiority designs to avoid exposing patients to less effective comparators in trials and bringing new medications to patients more efficiently.

A functional calcium-binding site in the metalloprotease domain of ADAMTS13.

ADAMTS13 regulates the multimeric size of von Willebrand factor (VWF). Its function is highly dependent upon Ca(2+) ions. Using the initial rates of substrate (VWF115, VWF residues 1554-1668) proteolysis by ADAMTS13 preincubated with varying Ca(2+) concentrations, a high-affinity functional ADAMTS13 Ca(2+)-binding site was suggested with K(D(app)) of 80 muM (+/- 15 muM) corroborating a previously reported study. When Glu83 or Asp173 (residues involved in a predicted Ca(2+)-binding site in the ADAMTS13 metalloprotease domain) were mutated to alanine, Ca(2+) dependence of proteolysis of the substrate was unaffected. Consequently, we sought and identified a candidate Ca(2+)-binding site in proximity to the ADAMTS13 active site, potentially comprising Glu184, Asp187, and Glu212. Mutagenesis of these residues within this site to alanine dramatically attenuated the K(D(app)) for Ca(2+) of ADAMTS13, and for D187A and E212A also reduced the V(max) to approximately 25% of normal. Kinetic analysis of the Asp187 mutant in the presence of excess Ca(2+) revealed an approximately 13-fold reduction in specificity constant, k(cat)/K(m), contributed by changes in both K(m) and k(cat). These results were corroborated using plasma-purified VWF as a substrate. Together, our results demonstrate that a major influence of Ca(2+) upon ADAMTS13 function is mediated through binding to a high-affinity site adjacent to its active site cleft.

Median Nerve and Ulnar Nerve Entrapment with Cubital Tunnel Syndrome in a Hemodialysis Patient Following Creation of an Arteriovenous Fistula.

Neurological and vascular complications associated with creation of arteriovenous access need to be recognized promptly to deliver appropriate interventions for relief of symptoms and avoid loss of function of the involved extremity. We present here a 55-year-old female with end-stage renal disease on hemodialysis secondary to diabetic nephropathy who had a surgical creation of first stage of the brachial artery-basilic vein fistula in the left arm. She subsequently developed pain and weakness of the left arm which was diagnosed as median and ulnar nerve entrapment. She was treated with surgical nerve release and neurolysis and her symptoms improved.

Bartonella-Associated Endocarditis with Severe Active Crescentic Glomerulonephritis and Acute Renal Failure.

We report a case of severe acute kidney failure due to crescentic glomerulonephritis who presented initially with culture-negative endocarditis with vegetations on the aortic valve. Anti-nuclear and anti-phospholipid antibodies were positive with initially negative anti-neutrophil cytoplasmic antibodies (ANCAs). Kidney biopsy revealed severe acute crescentic glomerulonephritis with mesangial immune complex deposition. PR3-ANCA subsequently become positive, and the patient developed worsening kidney failure requiring hemodialysis. This case illustrates that Bartonella can present as culture-negative endocarditis with severe crescentic glomerulonephritis with positive PR-3 ANCAs and can mimic ANCA-associated crescentic glomerulonephritis.

Kidney bone disease and mortality in CKD: revisiting the role of vitamin D, calcimimetics, alkaline phosphatase, and minerals.

Recent evidence suggests that the traditional syndromes known as renal osteodystrophy, secondary hyperparathyroidism, and vitamin D deficiency are related to mortality in persons with moderate to advanced chronic kidney disease (CKD). The so-called 'kidney bone disease', also known as 'mineral and bone disorders', is defined to include bone disorders, mineral disarrays, and vascular calcification. We have identified 14 common and clinically relevant conditions of contemporary nature that are related to the kidney bone disease, including calcitriol (active vitamin D) deficiency, 25(OH)-vitamin D deficiency, biochemical hyperparathyroidism, relatively low parathyroid hormone (PTH) level, increased serum alkaline phosphatase (hyperphosphatasemia), elevated fibroblast growth factor (FGF)-23, high turnover bone disease, adynamic bone disease, uremic osteoporosis, vascular calcification, hyper- and hypophosphatemia, and hyper- and hypocalcemia. We present a critical review of these 14 conditions with emphasis on patient survival and other pertinent clinical outcomes. We also review unresolved controversies surrounding the management of these conditions by administration of nutritional vitamin D (ergocalciferol and cholecalciferol), vitamin D receptor activators (calcitriol, alphacalcidiol, doxercalciferol), D-mimetics (paricalcitol, maxacalcitol), calcimimetics (cinacalcet), recombinant PTH (teriparatide), and receptor activator of nuclear factor-kappaB ligand modulators (denosumab); compare mortality predictability of PTH and alkaline phosphatase; and examine potential risks of bone disorders and mineral disarrays in CKD patients.

Long-term prognostic value of longitudinal measurements of blood neurofilament levels.

OBJECTIVE: To assess the long-term prognostic value of an integral of longitudinal measurements of plasma neurofilament light chain levels (NfLlong) over 12 and 24 months vs single neurofilament light chain (NfL) measurements in patients with relapsing-remitting MS (RRMS) and its additional value when combined with clinical and MRI measures. METHODS: This analysis included continuously fingolimod-treated patients with RRMS from the 24-month FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS)/12-month Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS) phase 3 trials and their long-term extension, LONGTERMS. Patients were classified into high (≥30 pg/mL, n = 110) and low (<30 pg/mL, n = 164) NfL categories based on the baseline (BL) NfL value or the geometric mean NfLlong calculated over 12 and 24 months to predict disability-related outcomes and brain volume loss (BVL). The additional prognostic value of NfL was quantified using the area under the receiver operating characteristic (ROC) curve. RESULTS: A single high (vs low) NfL measure at BL was prognostic of a higher risk of reaching Expanded Disability Status Scale (EDSS) score ≥4 earlier (hazard ratio [HR] = 2.19; 95% CI = 1.21-3.97) and higher BVL over 120 months (difference: -1.12%; 95% CI = -2.07 to -0.17). When NfLlong was measured over 24 months, high NfL was associated with a higher risk of reaching EDSS score ≥4 (HR = 7.91; 95% CI = 2.99-20.92), accelerated 6-month confirmed disability worsening (HR = 3.14; 95% CI = 1.38-7.11), and 20% worsening in the Timed 25-Foot Walk Test (HR = 3.05; 95% CI = 1.38-6.70). Area under the ROC curve was consistently highest in models combining NfL with clinical and MRI measures. CONCLUSIONS: NfLlong had a higher prognostic value than single NfL assessments on long-term outcomes in RRMS. Combining it with clinical and MRI measures increased sensitivity and specificity to predict long-term disease outcomes. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that NfLlong was more strongly associated with long-term outcomes than single NfL assessments in patients with RRMS.