Diagnostic delay of sarcoidosis: an integrated systematic review.

BACKGROUND: Sarcoidosis is a chronic inflammatory granulomatous disease of unknown cause. Delays in diagnosis can result in disease progression and poorer outcomes for patients. Our aim was to review the current literature to determine the overall diagnostic delay of sarcoidosis, factors associated with diagnostic delay, and the experiences of people with sarcoidosis of diagnostic delay. METHODS: Three databases (PubMed/Medline, Scopus, and ProQuest) and grey literature sources were searched. Random effects inverse variance meta-analysis was used to pool mean diagnostic delay in all types of sarcoidosis subgroup analysis. Diagnostic delay was defined as the time from reported onset of symptoms to diagnosis of sarcoidosis. RESULTS: We identified 374 titles, of which 29 studies were included in the review, with an overall sample of 1531 (694 females, 837 males). The overall mean diagnostic delay in all types of sarcoidosis was 7.93 months (95% CI 1.21 to 14.64 months). Meta-aggregation of factors related to diagnostic delay in the included studies identified three categories: (1) the complex and rare features of sarcoidosis, (2) healthcare factors and (3) patient-centred factors. Meta-aggregation of outcomes reported in case studies revealed that the three most frequent outcomes associated with diagnostic delay were: (1) incorrect diagnosis, (2) incorrect treatment and (3) development of complications/disease progression. There was no significant difference in diagnostic delay between countries with gatekeeper health systems (where consumers are referred from a primary care clinician to specialist care) and countries with non-gatekeeper systems. No qualitative studies examining people's experiences of diagnostic delay were identified. CONCLUSION: The mean diagnostic delay for sarcoidosis is almost 8 months, which has objective consequences for patient management. On the other hand, there is a paucity of evidence about the experience of diagnostic delay in sarcoidosis and factors related to this. Gaining an understanding of people's experiences while seeking a diagnosis of sarcoidosis is vital to gain insight into factors that may contribute to delays, and subsequently inform strategies, tools and training activities aimed at increasing clinician and public awareness about this rare condition. TRIAL REGISTRATION: PROSPERO Registration number: CRD42022307236.

Decompression sickness followed by diabetic ketoacidosis and sepsis shock: an unusual case report.

Decompression sickness (DCS) is caused by abrupt changes in extracorporeal pressure with varying severity. Symptoms range from mild musculoskeletal pain to severe organ dysfunction and death, especially among patients with chronic underlying disease. Here, we report an unusual case of a 49-year-old man who experienced DCS after a dive to a depth of 38 meters. The patient's symptoms progressed, starting with mild physical discomfort that progressed to disturbance of consciousness on the second morning. During hospitalization, we identified that in addition to DCS, he had also developed diabetic ketoacidosis, septic shock, and rhabdomyolysis. After carefully balancing the benefits and risks, we decided to provide supportive treatment to sustain vital signs, including ventilation support, sugar-reducing therapy, fluid replacement, and anti-infection medications. We then administered delayed hyperbaric oxygen (HBO2) when his condition was stable. Ultimately, the patient recovered without any sequelae. This is the first case report of a diver suffering from DCS followed by diabetic ketoacidosis and septic shock. We have learned that when DCS and other critical illnesses are highly suspected, it is essential to assess the condition comprehensively and focus on the principal contradiction.

Peripheral Immune Profiles Predict ALS Progression in an Age- and Sex-Dependent Manner.

BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease whose pathobiology associates with peripheral blood immune cell levels and activation patterns in an age and sex-dependent manner. This study's objective was to identify immune profile associations with ALS progression, whether the associations are age and sex-specific, and whether immune profiles can predict a future disease course. METHODS: Flow cytometry immune profiles (a combination of 22 peripheral blood immune markers) were generated for 241 participants with ALS and linked to ALS progression, using progression-free survival, which is a composite combining the revised ALS Functional Rating Scale and survival. Participants were first grouped by immune profiles using unsupervised hierarchical clustering, and clusters were associated with subsequent progression-free survival. Next, individual immune markers were associated with progression-free survival using least absolute shrinkage and selection operator-Cox regression. Analyses were stratified by age and sex to identify demographic-specific immune mechanisms. Finally, random forest determined the predictive power of immune profiles on ALS progression in the whole population and again stratified by age and sex. RESULTS: Progression-free survival differed between clusters of participants with similar immune profiles, particularly reduced natural killer (NK)-cell activation associated with slower progression. Individual markers such as neutrophil levels and NK-cell NKp46 expression associated with faster ALS progression while overall NK-cell levels and NK-cell subpopulations associated with slower progression; the strength of these associations varied by age and sex. Adding these immune markers to prediction models dramatically increased short-term prediction compared with routine clinical prognostic variables alone, and the addition of NK-cell markers further improved the prediction accuracy in female participants. DISCUSSION: Specific immune profiles likely contribute to ALS progression in an age and sex-dependent manner, and peripheral immune markers enhance the prediction of short-term clinical outcomes. These findings suggest a complex milieu of immune profiles associated with ALS progression, and more detailed immunophenotyping in ALS will facilitate personalized immunotherapeutics in ALS.

The role and mechanism of TXNDC5 in disease progression.

Thioredoxin domain containing protein-5 (TXNDC5), also known as endothelial protein-disulfide isomerase (Endo-PDI), is confined to the endoplasmic reticulum through the structural endoplasmic reticulum retention signal (KDEL), is a member of the PDI protein family and is highly expressed in the hypoxic state. TXNDC5 can regulate the rate of disulfide bond formation, isomerization and degradation of target proteins through its function as a protein disulfide isomerase (PDI), thereby altering protein conformation, activity and improving protein stability. Several studies have shown that there is a significant correlation between TXNDC5 gene polymorphisms and genetic susceptibility to inflammatory diseases such as rheumatoid, fibrosis and tumors. In this paper, we detail the expression characteristics of TXNDC5 in a variety of diseases, summarize the mechanisms by which TXNDC5 promotes malignant disease progression, and summarize potential therapeutic strategies to target TXNDC5 for disease treatment.

Interpretations of Studies on SARS-CoV-2 Vaccination and Post-acute COVID-19 Sequelae.

This article discusses causal interpretations of epidemiologic studies of the effects of vaccination on sequelae after acute severe acute respiratory syndrome coronavirus 2 infection. To date, researchers have tried to answer several different research questions on this topic. While some studies assessed the impact of postinfection vaccination on the presence of or recovery from post-acute coronavirus disease 2019 syndrome, others quantified the association between preinfection vaccination and postacute sequelae conditional on becoming infected. However, the latter analysis does not have a causal interpretation, except under the principal stratification framework-that is, this comparison can only be interpreted as causal for a nondiscernible stratum of the population. As the epidemiology of coronavirus disease 2019 is now nearly entirely dominated by reinfections, including in vaccinated individuals, and possibly caused by different Omicron subvariants, it has become even more important to design studies on the effects of vaccination on postacute sequelae that address precise causal questions and quantify effects corresponding to implementable interventions.

Long-term Impact of Tropical Cyclones on Disease Exacerbation Among Children with Asthma in the Eastern United States, 2000-2018.

BACKGROUND: Tropical cyclones are associated with acute increases in mortality and morbidity, but few studies have examined their longer-term health consequences. We assessed whether tropical cyclones are associated with a higher frequency of symptom exacerbation among children with asthma in the following 12 months in eastern United States counties, 2000-2018. METHODS: We defined exposure to tropical cyclones as a maximum sustained windspeed >21 meters/second at the county center and used coarsened exact matching to match each exposed county to one or more unexposed counties. We used longitudinal, de-identified administrative claims data to estimate the county-level, monthly risk of experiencing at least one asthma exacerbation requiring medical attention among commercially insured children aged 5-17 with prior diagnosis of asthma. We used a difference-in-differences approach implemented via a Poisson fixed effects model to compare the risk of asthma exacerbation in the 12 months before versus after each storm in exposed versus unexposed counties. RESULTS: Across 43 tropical cyclones impacting the eastern United States, we did not observe evidence of an increase in the risk of symptom exacerbation in the 12 months following the storm (random-effects meta-analytic summary estimate: risk ratio = 1.03 [95% confidence interval = 0.96, 1.10], I2 = 17%). However, certain storms, such as Hurricane Sandy, were associated with a higher risk of symptom exacerbation. CONCLUSIONS: These findings are consistent with the hypothesis that some tropical cyclones are detrimental to children's respiratory health. However, tropical cyclones were not associated in aggregate with long-term exacerbation of clinically apparent asthma symptoms among a population of children with commercial health insurance.

Disease Course of Clinically Isolated Optic Neuritis.

BACKGROUND AND OBJECTIVES: Optic neuritis is the most common optic neuropathy in young adults and a frequent manifestation of multiple sclerosis. Its clinical course is pertinent to the design of visual pathway neuroprotection trials. METHODS: This is a secondary analysis of longitudinal data from the TONE trial, which included 103 patients from 12 German academic tertiary centers with acute unilateral optic neuritis as a clinically isolated syndrome and baseline high-contrast visual acuity <0.5 decimal. Patients were randomized to 1,000 mg methylprednisolone i.v./d plus either erythropoietin (33,000 IU/d) or placebo (saline solution) for 3 days. They were followed up at standardized intervals with a battery of tests including high-contrast visual acuity, low-contrast letter acuity, contrast sensitivity, visual fields, visual evoked potentials, and retinal optical coherence tomography. At 6 months, participants answered a standardized questionnaire on vision-related quality of life (NEI-VFQ 25). We describe the disease course with mixed-effects piecewise linear models and calculate structure-function correlations using Pearson r. Because erythropoietin had no effect on the visual system, we use pooled (treatment-agnostic) data. RESULTS: Patients experienced initial rapid and then decelerating improvements of visual function with thinning of inner and thickening of outer retinal layers. At 6 months, visual parameters were positively correlated with inner and negatively correlated with outer retinal thickness changes. Peripapillary retinal nerve fiber layer thinning predominantly occurred in sectors without previous swelling. At 6 months, macular ganglion cell and inner plexiform layer thinning was weakly correlated with the P100 peak time (r = -0.11) and moderately correlated with the amplitude of visual evoked potentials (r = 0.35). Only functional outcomes were at least moderately correlated with vision-related quality of life. DISCUSSION: The longitudinal data from this large study cohort may serve as a reference for the clinical course of acute optic neuritis. The pattern of correlation between visual evoked potentials and inner retinal thinning may argue that the latter is mostly due to ganglion cell loss, rather than dysfunction. Visual pathway neuroprotection trials with functional outcomes are needed to confirm that candidate drugs will benefit patients' vision-related quality of life. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov, NCT01962571.

Hormonal basis of brain fog in cancer treatment.

The cognitive side effects of cancer treatment are common, but no targeted therapy exists yet to treat or prevent such neurological sequelae. We explore the role of hormones as mediators between cancer therapy and cognitive impairment, discussing potential future directions.

A Potential Role of Interleukin-5 in the Pathogenesis and Progression of Amyotrophic Lateral Sclerosis: A New Molecular Perspective.

Cumulative data suggest that neuroinflammation plays a prominent role in amyotrophic lateral sclerosis (ALS) pathogenesis. The purpose of this work was to assess if patients with ALS present a specific peripheral cytokine profile and if it correlates with neurological disability assessed by ALSFRS-R, the rate of disease progression, and the pattern of disease progression (horizontal spreading [HSP] versus vertical spreading [VSP]). We determined the levels of 15 cytokines in the blood of 59 patients with ALS and 40 controls. We identified a positive correlation between levels of pro-inflammatory cytokines (interleukin [IL]-17F, IL-33, IL-31) and the age of ALS patients, as well as a positive correlation between IL-12p/70 and survival from ALS onset and ALS diagnosis. Additionally, there was a positive correlation between the ALSFRS-R score in the upper limb and respiratory domain and IL-5 levels. In our ALS cohort, the spreading pattern was 42% horizontal and 58% vertical, with patients with VSP showing a faster rate of ALS progression. Furthermore, we identified a negative correlation between IL-5 levels and the rate of disease progression, as well as a positive correlation between IL-5 and HSP of ALS. To the best of our knowledge, this is the first study reporting a "protective" role of IL-5 in ALS.

The Influence of Microglia on Neuroplasticity and Long-Term Cognitive Sequelae in Long COVID: Impacts on Brain Development and Beyond.

Microglial cells, the immune cells of the central nervous system, are key elements regulating brain development and brain health. These cells are fully responsive to stressors, microenvironmental alterations and are actively involved in the construction of neural circuits in children and the ability to undergo full experience-dependent plasticity in adults. Since neuroinflammation is a known key element in the pathogenesis of COVID-19, one might expect the dysregulation of microglial function to severely impact both functional and structural plasticity, leading to the cognitive sequelae that appear in the pathogenesis of Long COVID. Therefore, understanding this complex scenario is mandatory for establishing the possible molecular mechanisms related to these symptoms. In the present review, we will discuss Long COVID and its association with reduced levels of BDNF, altered crosstalk between circulating immune cells and microglia, increased levels of inflammasomes, cytokines and chemokines, as well as the alterations in signaling pathways that impact neural synaptic remodeling and plasticity, such as fractalkines, the complement system, the expression of SIRPα and CD47 molecules and altered matrix remodeling. Together, these complex mechanisms may help us understand consequences of Long COVID for brain development and its association with altered brain plasticity, impacting learning disabilities, neurodevelopmental disorders, as well as cognitive decline in adults.

Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations.

In the last two decades, alpha-synuclein (alpha-syn) assumed a prominent role as a major component and seeding structure of Lewy bodies (LBs). This concept is driving ongoing research on the pathophysiology of Parkinson's disease (PD). In line with this, alpha-syn is considered to be the guilty protein in the disease process, and it may be targeted through precision medicine to modify disease progression. Therefore, designing specific tools to block the aggregation and spreading of alpha-syn represents a major effort in the development of disease-modifying therapies in PD. The present article analyzes concrete evidence about the significance of alpha-syn within LBs. In this effort, some dogmas are challenged. This concerns the question of whether alpha-syn is more abundant compared with other proteins within LBs. Again, the occurrence of alpha-syn compared with non-protein constituents is scrutinized. Finally, the prominent role of alpha-syn in seeding LBs as the guilty structure causing PD is questioned. These revisited concepts may be helpful in the process of validating which proteins, organelles, and pathways are likely to be involved in the damage to meso-striatal dopamine neurons and other brain regions involved in PD.

Conventional Cytogenetic Analysis and Array CGH + SNP Identify Essential Thrombocythemia and Prefibrotic Primary Myelofibrosis Patients Who Are at Risk for Disease Progression.

The Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) are a heterogeneous group of clonal hematopoietic malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (prePMF). In this study, we retrospectively reviewed the karyotypes from conventional cytogenetics (CC) and array Comparative Genomic Hybridization + Single Nucleotide Polymorphism (aCGH + SNP) in patients with ET or prePMF to determine whether the combined analysis of both methodologies can identify patients who may be at a higher risk of disease progression. We performed a comprehensive genomic review on 169 patients with a clinical diagnosis of ET (154 patients) or prePMF (15 patients). Genomic alterations detected by CC or array-CGH + SNP were detected in 36% of patients. In patients who progressed, 68% had an abnormal genomic finding by either technology. There was a shorter progression-free survival (PFS) among patients who were cytogenetically abnormal or who were cytogenetically normal but had an abnormal aCGH + SNP result. Leveraging the ability to detect submicroscopic copy number alterations and regions of copy neutral-loss of heterozygosity, we identified a higher number of patients harboring genomic abnormalities than previously reported. These results underscore the importance of genomic analysis in prognostication and provide valuable information for clinical management and treatment decisions.

Research progress of post-acute sequelae after SARS-CoV-2 infection.

SARS-CoV-2 has spread rapidly worldwide and infected hundreds of millions of people worldwide. With the increasing number of COVID-19 patients discharged from hospitals, the emergence of its associated complications, sequelae, has become a new global health crisis secondary to acute infection. For the time being, such complications and sequelae are collectively called "Post-acute sequelae after SARS-CoV-2 infection (PASC)", also referred to as "long COVID" syndrome. Similar to the acute infection period of COVID-19, there is also heterogeneity in PASC. This article reviews the various long-term complications and sequelae observed in multiple organ systems caused by COVID-19, pathophysiological mechanisms, diagnosis, and treatment of PASC, aiming to raise awareness of PASC and optimize management strategies.

Minimal clinically important differences in six-minute walking distance in late-onset Pompe disease.

BACKGROUND: The minimal clinically important difference (MCID) is the smallest change in outcome that physicians or patients would consider meaningful and is relevant when evaluating disease progression or the efficacy of interventions. Studies of patients with late-onset Pompe disease (LOPD) have used the 6-min walk distance (6MWD) as an endpoint to assess motor function. However, an MCID for 6MWD (% predicted and meters) has yet to be established in LOPD. The objective of the study was to derive 6MWD MCID (% predicted and meters) with different analysis methods and for subgroups of different disease severity for LOPD. METHODS: Data from the PROPEL trial were used to calculate 6MWD MCID in the overall PROPEL population and subgroups of baseline severity as assessed by walking distance and body mass index (BMI), using anchor- and distribution-based approaches. RESULTS: The 6MWD MCIDs varied widely, depending on the method and subgroup, ranging from 2.27%-8.11% predicted for the overall LOPD population (23.7 m-57.2 m). For patients with baseline 6MWD < 150 m, MCIDs ranged from -0.74%-3.37% (-2.1 m-11.3 m). MCIDs increased with distance walked at baseline until a plateau was reached. For BMI subgroups, the MCIDs were generally lowest in obese patients. CONCLUSION: Our analysis shows that MCID depends on the chosen method and disease severity. The findings suggest that applying a single MCID to all patients can be misleading; consequently, a range of possible MCIDs should be considered. This may also be highly relevant for other neuromuscular diseases. This study provides a range of 6MWD MCIDs for LOPD, with lower MCIDs for more severe patients.

Individualised treatment of COPD exacerbations using biomarkers.

This review highlights key aspects of treating chronic obstructive pulmonary disease (COPD) exacerbation, focusing on the optimisation of systemic corticosteroid and antibiotic use through personalised treatment using biomarkers. Eosinophil-guided therapy reduces corticosteroid usage which might reduce side effects, while procalcitonin-guided therapy contributes to reduced antibiotic consumption. These approaches, documented through well-conducted randomized controlled trials, suggest the possibility of enhancing COPD exacerbation management, reducing potential side effects, and addressing concerns related to antibiotic resistance.

Ductular Reactions in Liver Injury, Regeneration, and Disease Progression-An Overview.

Ductular reaction (DR) is a complex cellular response that occurs in the liver during chronic injuries. DR mainly consists of hyper-proliferative or reactive cholangiocytes and, to a lesser extent, de-differentiated hepatocytes and liver progenitors presenting a close spatial interaction with periportal mesenchyme and immune cells. The underlying pathology of DRs leads to extensive tissue remodeling in chronic liver diseases. DR initiates as a tissue-regeneration mechanism in the liver; however, its close association with progressive fibrosis and inflammation in many chronic liver diseases makes it a more complicated pathological response than a simple regenerative process. An in-depth understanding of the cellular physiology of DRs and their contribution to tissue repair, inflammation, and progressive fibrosis can help scientists develop cell-type specific targeted therapies to manage liver fibrosis and chronic liver diseases effectively.

The personal impact of living with a myeloproliferative neoplasm.

OBJECTIVE: The aim of this study is to gain insight into the physical, psychological and social impact of having a myeloproliferative neoplasm (MPN), a rare type of cancer with an often chronic course. METHODS: An online survey was conducted among 455 Dutch MPN patients (62.7% female, age M 63) to explore the impact of the disease by measuring the MPN symptom burden (MPN-SAF TSS) and quality of life (QoL) (EORTC QLQ-C30) and its subscales within a hierarchical QoL model. We examined differences in MPN symptom burden and QoL in relation to sociodemographic and disease-related factors. Hierarchical regression analysis was used to explain variances in QoL. RESULTS: Most patients (97%) experienced MPN-related health complaints, with a significantly higher MPN symptom burden in women (M 31.50) compared to men (M 24.10). Regarding to fatigue and cognitive functioning MPN patients suffered more compared to a reference group of other cancers. MPN subtype or type of treatment did not show significant differences in MPN symptom burden or QoL. However, experiencing side effects, complications or comorbidities significantly negatively affected MPN symptom burden and QoL. 48.8% of patients reported that MPN affected their ability to work. The explained variance in overall QoL was 58%, most importantly by disease progression, comorbidities, MPN symptom burden and role, emotional and social functioning. CONCLUSION: This study revealed that having an MPN has a negative impact on several domains of QoL. Symptom assessment and support should be included in the healthcare management of MPN patients.

Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance : A Cohort Study Nested in a Clinical Trial.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management. OBJECTIVE: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model. DESIGN: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597). SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. MEASUREMENTS: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater. RESULTS: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds. LIMITATION: The prediction model will require external validation. CONCLUSION: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology. PRIMARY FUNDING SOURCE: International Myeloma Foundation and the European Research Council.

Association of Albuminuria With Chronic Kidney Disease Progression in Persons With Chronic Kidney Disease and Normoalbuminuria : A Cohort Study.

BACKGROUND: Albuminuria is a major risk factor for chronic kidney disease (CKD) progression, especially when categorized as moderate (30 to 300 mg/g) or severe (>300 mg/g). However, there are limited data on the prognostic value of albuminuria within the normoalbuminuric range (<30 mg/g) in persons with CKD. OBJECTIVE: To estimate the increase in the cumulative incidence of CKD progression with greater baseline levels of albuminuria among persons with CKD who had normoalbuminuria (<30 mg/g). DESIGN: Multicenter prospective cohort study. SETTING: 7 U.S. clinical centers. PARTICIPANTS: 1629 participants meeting criteria from the CRIC (Chronic Renal Insufficiency Cohort) study with CKD (estimated glomerular filtration rate [eGFR], 20 to 70 mL/min/1.73 m2) and urine albumin-creatinine ratio (UACR) less than 30 mg/g. MEASUREMENTS: Baseline spot urine albumin divided by spot urine creatinine to calculate UACR as the exposure variable. The 10-year adjusted cumulative incidences of CKD progression (composite of 50% eGFR decline or kidney failure [dialysis or kidney transplantation]) from confounder adjusted survival curves using the G-formula. RESULTS: Over a median follow-up of 9.8 years, 182 of 1629 participants experienced CKD progression. The 10-year adjusted cumulative incidences of CKD progression were 8.7% (95% CI, 5.9% to 11.6%), 11.5% (CI, 8.8% to 14.3%), and 19.5% (CI, 15.4% to 23.5%) for UACR levels of 0 to less than 5 mg/g, 5 to less than 15 mg/g, and 15 mg/g or more, respectively. Comparing persons with UACR 15 mg/g or more to those with UACR 5 to less than 15 mg/g and 0 to less than 5 mg/g, the absolute risk differences were 7.9% (CI, 3.0% to 12.7%) and 10.7% (CI, 5.8% to 15.6%), respectively. The 10-year adjusted cumulative incidence increased linearly based on baseline UACR levels. LIMITATION: UACR was measured once. CONCLUSION: Persons with CKD and normoalbuminuria (<30 mg/g) had excess risk for CKD progression, which increased in a linear fashion with higher levels of albuminuria. PRIMARY FUNDING SOURCE: None.