Rapid Progressors Research Articles

Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons With Amyotrophic Lateral Sclerosis.

Background and ObjectivesIn a phase 1 amyotrophic lateral sclerosis (ALS) study, autologous infusions of expanded regulatory T-lymphocytes (Tregs) combined with subcutaneous interleukin (IL)-2 were safe and well tolerated. Treg suppressive function increased and disease progression stabilized during the study. The present study was conducted to confirm the reliability of these results.MethodsParticipants with ALS underwent leukapheresis, and their Tregs were isolated and expanded in a current Good Manufacturing Practice facility. Seven participants were randomly assigned in a 1:1 ratio to receive Treg infusions (1 × 106 cells/kg) IV every 4 weeks and IL-2 (2 × 105 IU/m2) injections 3 times/wk or matching placebo in a 24-week randomized controlled trial (RCT). Six participants proceeded into a 24-week dose-escalation open-label extension (OLE). Two additional participants entered directly into the OLE. The OLE included dose escalation of Treg infusions to 2 × 106 cells/kg and 3 × 106 cells/kg at 4-week intervals.ResultsThe Treg/IL-2 treatments were safe and well tolerated, and Treg suppressive function was higher in the active group of the RCT. A meaningful evaluation of progression rates in the RCT between the placebo and active groups was not possible due to the limited number of enrolled participants aggravated by the COVID-19 pandemic. In the 24-week OLE, the Treg/IL-2 treatments were also safe and well tolerated in 8 participants who completed the escalating doses. Treg suppressive function and numbers were increased compared with baseline. Six of 8 participants changed by an average of −2.7 points per the ALS Functional Rating Scale–Revised, whereas the other 2 changed by an average of −10.5 points. Elevated levels of 2 markers of peripheral inflammation (IL-17C and IL-17F) and 2 markers of oxidative stress (oxidized low-density lipoprotein receptor 1 and oxidized LDL) were present in the 2 rapidly progressing participants but not in the slower progressing group.DiscussionTreg/IL-2 treatments were safe and well tolerated in the RCT and OLE with higher Treg suppressive function. During the OLE, 6 of 8 participants showed slow to no progression. The 2 of 8 rapid progressors had elevated markers of oxidative stress and inflammation, which may help delineate responsiveness to therapy. Whether Treg/IL-2 treatments can slow disease progression requires a larger clinical study (ClinicalTrials.gov number, NCT04055623).Classification of EvidenceThis study provides Class IV evidence that Treg infusions and IL-2 injections are safe and effective for patients with ALS.

Chitotriosidase 1 in the cerebrospinal fluid as a putative biomarker for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) progression

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurodegenerative disease that affects motor, urinary, intestinal, and sensory functions. Typically, HAM/TSP is slowly progressive, but it may vary from limited motor disability after decades (very slow progression) to loss of motor function in a few years from disease onset (rapid). In this study, we aimed to identify prognostic biomarkers for HAM/TSP to support patient management. Thus, proteomic analysis of the cerebrospinal fluid (CSF) was performed with samples from HTLV-1 asymptomatic carriers (AC) (n=13) and HAM/TSP patients (n=21) with rapid, typical, and very slow progression using quantitative label-free liquid chromatography/tandem mass spectrometry. Enrichment analyses were also carried out to identify key biological processes associated with distinct neurological conditions in HTLV-1 infection. Candidate biomarkers were validated by ELISA in paired CSF and serum samples, and samples from HTLV-1-seronegative individuals (n=9) were used as controls. CSF analysis identified 602 proteins. Leukocyte/cell activation, immune response processes and neurodegeneration pathways were enriched in rapid progressors. Conversely, HTLV-1 AC and HAM/TSP patients with typical and very slow progression had enriched processes for nervous system development. Differential expression analysis showed that soluble vascular cell adhesion molecule 1 (sVCAM-1), chitotriosidase 1 (CHIT1), and cathepsin C (CTSC) were upregulated in HAM/TSP. However, only CHIT1 was significantly elevated after validation, particularly in HAM/TSP rapid progressors. In contrast, none of these biomarkers were altered in serum. Additionally, CSF CHIT1 levels in HAM/TSP patients positively correlated with the speed of HAM/TSP progression, defined as points in the IPEC-2 HAM/TSP disability scale per year of disease, and with CSF levels of phosphorylated neurofilament heavy chain, neopterin, CXCL5, CXCL10, and CXCL11. In conclusion, higher CSF levels of CHIT1 were associated with HAM/TSP rapid progression and correlated with other biomarkers of neuroinflammation and neurodegeneration. Therefore, we propose CHIT1 as an additional or alternative CSF biomarker to identify HAM/TSP patients with a worse prognosis.

The potential role of exosomal miRNAs and membrane proteins in acute HIV-infected people.

Exosomes play an important role during human immunodeficiency virus (HIV) acute infection. Yet, information regarding its cargo and its association with HIV rapid progressors (RPs) and typical progressors (TPs) remain largely unknown. In this study, exosomal miRNAs sequencing and mass cytometry were used to identify differential exosomal miRNAs and membrane proteins that participate in the pathogenesis of TPs and RPs. We discovered that miR-144-5p, miR-1180-3p, miR-451a, miR-362-5p, and miR-625-5p are associated with the TPs and miR-362-5p with the RPs. Decreased autophagy, amino acid metabolism, immune response, and IL-6 are closely related to RPs. In addition, SP1 was selected as the most significant transcription factor (TF) associated with disease progression. CD49D, CD5, CCR5, CD40, CD14, and CD86 were selected as the differential exosomal membrane proteins between TPs and RPs. This study provides valuable information for clarifying the mechanism in people with acute HIV infection.

Machine-Identified Patterns of Visual Field Loss and an Association with Rapid Progression in the Ocular Hypertension Treatment Study

To identify patterns of visual field (VF) loss based on unsupervised machine learning and to identify patterns that are associated with rapid progression. Cross-sectional and longitudinal study. A total of 2231 abnormal VFs from 205 eyes of 176 Ocular Hypertension Treatment Study (OHTS) participants followed over approximately 16 years. Visual fields were assessed by an unsupervised deep archetypal analysis algorithm and an OHTS-certified VF reader to identify prevalent patterns of VF loss. Machine-identified patterns of glaucoma damage were compared against those patterns previously identified (expert-identified) in the OHTS in 2003. Based on the longitudinal VFs of each eye, VF loss patterns that were strongly associated with rapid glaucoma progression were identified. Machine-expert correspondence and type of patterns of VF loss associated with rapid progression. The average VF mean deviation (MD) at conversion to glaucoma was-2.7 decibels (dB) (standard deviation [SD]= 2.4 dB), whereas the average MD of the eyes at the last visit was-5.2 dB (SD= 5.5 dB). Fifty out of 205 eyes had MD rate of-1 dB/year or worse and were considered rapid progressors. Eighteen machine-identified patterns of VF loss were compared with expert-identified patterns, in which 13 patterns of VF loss were similar. The most prevalent expert-identified patterns included partial arcuate, paracentral, and nasal step defects, and the most prevalent machine-identified patterns included temporal wedge, partial arcuate, nasal step, and paracentral VF defects. One of the machine-identified patterns of VF loss predicted future rapid VF progression after adjustment for age, sex, and initial MD. An automated machine learning system can identify patterns of VF loss and could provide objective and reproducible nomenclature for characterizing early signs of visual defects and rapid progression in patients with glaucoma.

Downregulation of TCF1 in HIV Infection Impairs T-cell Proliferative Capacity by Disrupting Mitochondrial Function.

BackgroundDespite the benefits of antiretroviral therapy (ART) for people with HIV, T-cell dysfunction cannot be fully restored. Metabolic dysregulation is associated with dysfunction of HIV-1-specific T-cells. Exploration of the factors regulating metabolic fitness can help reverse T-cell dysfunction and provide new insights into the underlying mechanism.MethodsIn this study, HIV-infected individuals and HIV-negative control individuals (NCs) were enrolled. T-cell factor (TCF)1 expression in cells was determined by quantitative reverse-transcriptase polymerase chain reaction and flow cytometry. Relevant microarray data from the GEO database were analyzed to explore the underlying mechanism. The effects of TCF1 on T-cell function and metabolic function were assessed in vitro.ResultsTCF7 mRNA expression in peripheral blood mononuclear cells was downregulated in rapid progressors compared with long-term non-progressors individuals and NCs. TCF1 expression on CD4+ and CD8+ T-cells was downregulated in treatment-naïve HIV-infected individuals compared with NCs. Interleukin (IL)2 production and proliferative capacity were impaired in TCF1 knockdown T-cells. Moreover, glycolytic capacity and mitochondrial respiratory function were decreased in TCF1 knockdown T-cells, and depolarized mitochondria were increased in TCF1 knockdown T-cells.ConclusionDownregulation of TCF1 in HIV infection impairs T-cell proliferative capacity by disrupting mitochondrial function. These findings highlight the metabolic regulation as a pivotal mechanism of TCF1 in the regulation of T-cell dysfunction.

Identification of osteopontin as a urinary biomarker for autosomal dominant polycystic kidney disease progression.

Autosomal dominant polycystic kidney disease (ADPKD), one of the most common human monogenic diseases, is characterized by the presence of numerous fluid-filled renal cysts and is a leading cause of end-stage renal disease (ESRD). Urinary biomarkers may be useful for predicting the variable course of ADPKD progression from cyst growth to ESRD. To identify candidate urinary biomarkers of ADPKD progression, we used CRISPR/Cas9 genome editing to generate porcine fibroblasts with mono- and biallelic ADPKD gene knockout (PKD2+/- and PKD2-/-, respectively). We then performed RNA-sequencing analysis on these cells. Levels of osteopontin (OPN), which is expressed by renal epithelial tubular cells and excreted into urine, were reduced in PKD2-/- cells but not in PKD2+/- cells. OPN levels were also reduced in the renal cyst cells of ADPKD patients. Next, we investigated whether OPN excretion was decreased in patients with ADPKD via enzyme-linked immunosorbent assay. OPN levels excreted into renal cyst cell culture media and urine from ADPKD patients were decreased. To investigate whether OPN can predict the rate of ADPKD progression, we compared urinary excretion of OPN in ADPKD patients with slow progression and those with rapid progression. Those with rapid progression had an estimated glomerular filtration rate of >60 mL/min/1.73 m2 . Urinary OPN excretion levels were lower in rapid progressors than in slow progressors. These findings suggest that OPN is a useful urinary biomarker for predicting ADPKD progression.

Efficacy and safety study of fotemustine and bevacizumab in patients with recurrent glioblastoma.

e14041 Background: Glioblastoma (GBM) is highly vascularized tumor with elevated expression of vascular endothelial growth factor (VEGF). Bevacizumab (Bz) is a humanized monoclonal antibody against VEGF, which alone or associated with chemotherapy has obtained optimal results. However, the most suitable combination with bevacizumab is yet unknown. The objective of our study is to evaluate the efficacy and safety of Bz and fotemustine (Ft) in patients (pts) with recurrent GBM of the Huelva area and to compare our results with those published in the phase II study of the Italian Association of Neuro-oncology (AINO). Methods: Observational and descriptive study of the combination of Ft-Bz in GBM at first relapse after standard radiotherapy and TMZ concomitant in the hospital area of Huelva during the years 2010-2021. We used the same therapeutic scheme of the phase II study of AINO and the IBM SPSS Statistics 22 program to analyze the variables. Results: 42 pts were treated, 16 women and 25 men. Median age 52 years. ECOG 0-1 in 85.4%. 65.9% and 92.7% received antiepileptics and corticosteroids, respectively. In 90.2%, methylation status of the promoter of O6-methylguanine-DNA methyltransferase (MGMT) was not evaluated. Previously, 56.1% of the pts underwent total/subtotal resection, 29.3% partial and 14.6% were not resected, followed by concomitant radiotherapy and temozolamide in 100% of cases. 35.7% relapsed in less than 3 months after adjuvant treatment. 61% presented unifocal relapse and 39% multifocal. 46.3% of the pts had stable disease, 24.4% partial response and 2.4% complete response. 22% presented grade 3-4 toxicity. The most frequent toxicities are listed in the table. The median progression-free survival (PFS) was 6 months (95% CI 4.18-7.82) and the median overall survival (OS) was 7 months (95% CI 4.22-9.77). Conclusions: The results obtained in our study were similar to those of other previously published studies of Bz in combination with Ft. Although PFS was slightly higher than the phase II study AINO, OS was lower, probably due to the inclusion of a high rate of rapid progressors pts. Treatment tolerance was similar to that in the phase II study AINO. An increase in hematologic adverse events stands out in our pts. Therefore, this scheme can be a valid alternative in the management of recurrent GBM.[Table: see text]

Transactive Response DNA-Binding Protein (TARDBP/TDP-43) Regulates Cell Permissivity to HIV-1 Infection by Acting on HDAC6.

The transactive response DNA-binding protein (TARDBP/TDP-43) influences the processing of diverse transcripts, including that of histone deacetylase 6 (HDAC6). Here, we assessed TDP-43 activity in terms of regulating CD4+ T-cell permissivity to HIV-1 infection. We observed that overexpression of wt-TDP-43 increased both mRNA and protein levels of HDAC6, resulting in impaired HIV-1 infection independently of the viral envelope glycoprotein complex (Env) tropism. Consistently, using an HIV-1 Env-mediated cell-to-cell fusion model, the overexpression of TDP-43 levels negatively affected viral Env fusion capacity. Silencing of endogenous TDP-43 significantly decreased HDAC6 levels and increased the fusogenic and infection activities of the HIV-1 Env. Using pseudovirus bearing primary viral Envs from HIV-1 individuals, overexpression of wt-TDP-43 strongly reduced the infection activity of Envs from viremic non-progressors (VNP) and rapid progressors (RP) patients down to the levels of the inefficient HIV-1 Envs observed in long-term non-progressor elite controllers (LTNP-EC). On the contrary, silencing endogenous TDP-43 significantly favored the infectivity of primary Envs from VNP and RP individuals, and notably increased the infection of those from LTNP-EC. Taken together, our results indicate that TDP-43 shapes cell permissivity to HIV-1 infection, affecting viral Env fusion and infection capacities by altering the HDAC6 levels and associated tubulin-deacetylase anti-HIV-1 activity.

Radiomics-Based Image Phenotyping of Kidney Apparent Diffusion Coefficient Maps: Preliminary Feasibility & Efficacy.

Given the central role of interstitial fibrosis in disease progression in chronic kidney disease (CKD), a role for diffusion-weighted MRI has been pursued. We evaluated the feasibility and preliminary efficacy of using radiomic features to phenotype apparent diffusion coefficient (ADC) maps and hence to the clinical classification(s) of the participants. The study involved 40 individuals (10 healthy and 30 with CKD (eGFR < 60 mL/min/1.73 m2)). Machine learning methods, such as hierarchical clustering and logistic regression, were used. Clustering resulted in the identification of two clusters, one including all individuals with CKD (n = 17), while the second one included all the healthy volunteers (n = 10) and the remaining individuals with CKD (n = 13), resulting in 100% specificity. Logistic regression identified five radiomic features to classify participants as with CKD vs. healthy volunteers, with a sensitivity and specificity of 93% and 70%, respectively, and an AUC of 0.95. Similarly, four radiomic features were able to classify participants as rapid vs. non-rapid CKD progressors among the 30 individuals with CKD, with a sensitivity and specificity of 71% and 43%, respectively, and an AUC of 0.75. These promising preliminary data should support future studies with larger numbers of participants with varied disease severity and etiologies to improve performance.

Estimated GFR in autosomal dominant polycystic kidney disease: errors of an unpredictable method

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) causes about 10% of cases of end stage renal disease. Disease progression rate is heterogeneous. Tolvaptan is presently the only specific therapeutic option to slow kidney function decline in adults at risk of rapidly progressing ADPKD with chronic kidney disease (CKD) stages 1–4. Thus, a reliable evaluation of kidney function in patients with ADPKD is needed.MethodsWe evaluated the agreement between measured (mGFR) and estimated glomerular filtration rate (eGFR) by 61 formulas based on creatinine and/or cystatin-C (eGFR) in 226 ADPKD patients with diverse GFR values, from predialysis to glomerular hyperfiltration. Also, we evaluated whether incorrect categorization of CKD using eGFR may interfere with the indication and/or reimbursement of Tolvaptan treatment.ResultsNo formula showed acceptable agreement with mGFR. Total Deviation Index averaged about 50% for eGFR based on creatinine and/or cystatin-C, indicating that 90% of the estimations of GFR showed bounds of error of 50% when compared with mGFR. In 1 out of 4 cases with mGFR < 30 ml/min, eGFR provided estimations above this threshold. Also, in half of the cases with mGFR between 30 and 40 ml/min, formulas estimated values < 30 ml/min.ConclusionsThe evaluation of renal function with formulas in ADPKD patients is unreliable. Extreme deviation from real renal function is quite frequent. The consequences of this error deserve attention, especially in rapid progressors who may benefit from starting treatment with tolvaptan and in whom specific GFR thresholds are needed for the indication or reimbursement. Whenever possible, mGFR is recommended.Graphic abstract

Transcription Factor ZNF683 Inhibits SIV/HIV Replication through Regulating IFNγ Secretion of CD8+ T Cells.

Pulmonary microbial invasion frequently occurs during AIDS progression in HIV patients. Inflammatory cytokines and other immunoregulatory factors play important roles in this process. We previously established an AIDS model of SIVmac239 infection in northern pig-tailed macaques (NPMs), which were divided into rapid progressor (RP) and slow progressor (SP) groups according to their AIDS progression rates. In this study, we performed 16S rDNA and transcriptome sequencing of the lungs to reveal the molecular mechanism underlying the difference in progression rate between the RPs and SPs. We found that microbial invasion in the RP group was distinct from that in the SP group, showing marker flora of the Family XI, Enterococcus and Ezakiella, and more Lactobacilli. Through pulmonary transcriptome analysis, we found that the transcription factor ZNF683 had higher expression in the SP group than in the RP group. In subsequent functional experiments, we found that ZNF683 increased the proliferation and IFNγ secretion ability of CD8+ T cells, thus decreasing SIV or HIV replication, which may be related to AIDS progression in SIVmac239-infected NPMs. This study helps elucidate the various complexities of disease progression in HIV-1-infected individuals.

The Characteristics of the HIV-1 Env Glycoprotein Are Linked With Viral Pathogenesis.

The understanding of HIV-1 pathogenesis and clinical progression is incomplete due to the variable contribution of host, immune, and viral factors. The involvement of viral factors has been investigated in extreme clinical phenotypes from rapid progressors to long-term non-progressors (LTNPs). Among HIV-1 proteins, the envelope glycoprotein complex (Env) has been concentrated on in many studies for its important role in the immune response and in the first steps of viral replication. In this study, we analyzed the contribution of 41 Envs from 24 patients with different clinical progression rates and viral loads (VLs), LTNP-Elite Controllers (LTNP-ECs); Viremic LTNPs (vLTNPs), and non-controller individuals contemporary to LTNPs or recent, named Old and Modern progressors. We studied the Env expression, the fusion and cell-to-cell transfer capacities, as well as viral infectivity. The sequence and phylogenetic analysis of Envs were also performed. In every functional characteristic, the Envs from subjects with viral control (LTNP-ECs and vLTNPs) showed significant lower performance compared to those from the progressor individuals (Old and Modern). Regarding sequence analysis, the variable loops of the gp120 subunit of the Env (i.e., V2, V4, and mainly V5) of the progressor individuals showed longer and more glycosylated sequences than controller subjects. Therefore, HIV-1 Envs from virus of patients presenting viremic control and the non-progressor clinical phenotype showed poor viral functions and shorter sequences, whereas functional Envs were associated with virus of patients lacking virological control and with progressor clinical phenotypes. These correlations support the role of Env genotypic and phenotypic characteristics in the in vivo HIV-1 infection and pathogenesis.

Mayo imaging classification is a good predictor of rapid progress among Korean patients with autosomal dominant polycystic kidney disease: results from the KNOW-CKD study.

BackgroundMayo imaging classification (MIC) is a useful biomarker to predict disease progression in autosomal dominant polycystic kidney disease (ADPKD). This study was performed to validate MIC in the prediction of renal outcome in a prospective Korean ADPKD cohort and evaluate clinical parameters associated with rapid disease progression.MethodsA total of 178 ADPKD patients were enrolled and prospectively observed for an average duration of 6.2 ± 1.9 years. Rapid progressor was defined as MIC 1C through 1E while slow progressor was defined as 1A through 1B. Renal composite outcome (doubling of serum creatinine, 50% decline of estimated glomerular filtration rate [eGFR], or initiation of renal replacement therapy) as well as the annual percent change of height-adjusted total kidney volume (mHTKV-α) and eGFR decline (mGFR-α) were compared between groups.ResultsA total of 110 patients (61.8%) were classified as rapid progressors. These patients were younger and showed a higher proportion of male patients. Rapid progressor was an independent predictor for renal outcome (hazard ratio, 4.09; 95% confidence interval, 1.23–13.54; p = 0.02). The mGFR-α was greater in rapid progressors (–3.58 mL/min per year in 1C, –3.7 in 1D, and –4.52 in 1E) compared with that in slow progressors (–1.54 in 1A and –2.06 in 1B). The mHTKV-α was faster in rapid progressors (5.3% per year in 1C, 9.4% in 1D, and 11.7% in 1E) compared with that in slow progressors (1.2% in 1A and 3.8% in 1B).ConclusionMIC is a good predictive tool to define rapid progressors in Korean ADPKD patients.

Potential effect of tolvaptan on polycystic liver disease for patients with ADPKD meeting the Japanese criteria of tolvaptan use.

Polycystic liver disease (PLD) is a common extrarenal complication of autosomal dominant polycystic kidney disease (ADPKD), which causes compression-related syndrome and ultimately leads to liver dysfunction. Tolvaptan, a V2 receptor antagonist, is widely used to protect kidney function in ADPKD but its effect on PLD remains unknown. An observational cohort study was conducted to evaluate tolvaptan's effect on patients with PLD due to ADPKD. After screening 902 patients, we found the 107 ADPKD patients with PLD who met the criteria of tolvaptan use in Japan. Among them, tolvaptan was prescribed for 62 patients (tolvaptan group), while the other was defined as the non-tolvaptan group. Compared with the non-tolvaptan group, the tolvaptan group had larger height-adjusted total kidney volume (median 994(range 450-4152) mL/m, 513 (405-1928) mL/m, p = 0.01), lower albumin level (mean 3.9±SD 0.4 g/dL, 4.3±0.4g/dL, p<0.01), and higher serum creatinine level (1.2±0.4 mg/dL, 0.9±0.2 mg/dL, p<0.01). Although the median change in annual growth rate of total liver volume (TLV) was not statistically different between the tolvaptan group (-0.8 (-15.9, 16.7) %/year) and the non-tolvaptan group (1.7 (-15.6-18.7) %/year)(p = 0.52), 20 (43.5%) patients in the tolvaptan group experienced a decrease in the growth rate of TLV (responders). A multivariable logistic regression model adjusting for related variables showed that older age (odds ratio 1.15 [95% CI 1.01-1.32]) and a higher growth rate of TLV in the non-tolvaptan period (odds 1.45 95% CI 1.10-1.90) were significantly associated with responders. In conclusion, the change in annual growth rate of TLV in ADPKD patients taking tolvaptan was not statistically different compared with that in ADPKD patients without taking tolvaptan. However, tolvaptan may have the potential to suppress the growth rate of TLV in some PLD patients due to ADPKD, especially in older patients or those that are rapid progressors of PLD. Several limitations were included in this study, therefore well-designed prospective studies were required to confirm the effect of tolvaptan on PLD.

Potential Applications of Artificial Intelligence in Clinical Trials for Alzheimer's Disease.

Clinical trials for Alzheimer’s disease (AD) face multiple challenges, such as the high screen failure rate and the even allocation of heterogeneous participants. Artificial intelligence (AI), which has become a potent tool of modern science with the expansion in the volume, variety, and velocity of biological data, offers promising potential to address these issues in AD clinical trials. In this review, we introduce the current status of AD clinical trials and the topic of machine learning. Then, a comprehensive review is focused on the potential applications of AI in the steps of AD clinical trials, including the prediction of protein and MRI AD biomarkers in the prescreening process during eligibility assessment and the likelihood stratification of AD subjects into rapid and slow progressors in randomization. Finally, this review provides challenges, developments, and the future outlook on the integration of AI into AD clinical trials.

Medication Adherence, Complementary Medicine Usage and Progression of Diabetic Chronic Kidney Disease in Thais.

PurposeNon-adherence to medication is receiving more attention as a significant problem common to management of chronic diseases including diabetes and chronic kidney disease (CKD). This study was designed to assess the medication adherence and self-medication in a cohort of Thai patients with diabetic kidney disease, and its association with clinical outcomes.Patients and MethodsNon-dialysis patients with diabetic CKD visiting outpatient’s clinics of Siriraj Hospital, the largest tertiary care in Thailand, were asked for participation. Self-administered questionnaire was given to assess medication adherence (the 6-item-medication-taking-behavior measure in Thai), complementary medicine usage, and personal information. Clinical, pharmaceutical, and relevant laboratory data (at current and the last visit of around 12 months) were abstracted from the medical records.ResultsOf the 220 participants eligible (54.1% male, mean age 71.3), 50.9%, 24.1%, and 25% were classified as high-, medium-, and low-medication adherence, respectively. Overall, 24.1% reported self-usage of at least one type of herbal or complementary medicines. The most commonly identified items were cordyceps, cod liver oil, Nan Fui Chao, and turmeric (6 each), with unidentified Thai herbal mixture in 11. On multivariate analysis, late-stage CKD (stage IV–V) was the only independent predictor for low adherence (odds ratio (OR), 5.54; 95% confidence interval (CI), 2.82–10.88). Low adherence was associated with higher blood pressure, lower estimated glomerular filtrate rate (eGFR), and more eGFR decline with greater risk of being rapid CKD progressor (annual eGFR drop >5 mL/min/1.73 m2) [OR, 1.15; 95% CI, 1.06–1.25].ConclusionMedication taking behavior was a frequently encountered problem in Thai diabetic CKD patients. Increased medication non-adherence was independently predicted by stages of increasing CKD severity, and it was associated with poorer hypertensive control and kidney outcome. Targeting interventions to improve medication adherence should be an important strategy to slow CKD progression among patients with diabetic CKD.

Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P).

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were −13.8% (95% CI: −20.1–−7.1; p < 0.001) and −6.0% (95% CI: −12.8–1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085)

Comparative analysis of tools to predict rapid progression in autosomal dominant polycystic kidney disease.

ABSTRACTBackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and shows a wide phenotype. Only patients with rapid progression (RP) are included in clinical trials or are approved to receive disease-modifying drugs. This study aims at comparing different available predictive tools in ADPKD with the Mayo classification (MC) identification of rapid progressors based on high total kidney volume (TKV) according to age.MethodsA total of 164 ADPKD patients were recruited retrospectively from a single centre. The performance of diverse tools to identify RP defined as being in MC categories 1C–1E was assessed.ResultsA total of 118 patients were MC 1C–1E. The algorithm developed by the European Renal Association–European Dialysis and Transplant Association Working Group on Inherited Kidney Disorders/European Renal Best Practice had a low sensitivity in identifying MC 1C–1E. The sensitivity and specificity of TKV to predict RP depend on the cut-off used. A kidney length of >16.5 cm before age 45 years has high specificity but low sensitivity. Assessing the MC by ultrasonography had high levels of agreement with magnetic resonance imaging (MRI) data, especially for 1A, 1D and 1E. The estimated glomerular filtration rate (eGFR) decline was very sensitive but had low specificity. In contrast, the Predicting Renal Outcome in Polycystic Kidney Disease (PROPKD) score was very specific but had poor sensitivity. Having hypertension before 35 years of age is a good clinical predictor of MC 1C–1E. Family history can be of help in suggesting RP, but by itself it lacks sufficient sensitivity and specificity.ConclusionsThe MC by ultrasonography could be an option in hospitals with limited access to MRI as it performs well generally, and especially at the extremes of the MC, i.e. classes 1A, 1D and 1E. The eGFR decline is sensitive but not very specific when compared with the MC, whereas the PROPKD score is very specific but has low sensitivity. Integrating the different tools currently available to determine RP should facilitate the identification of rapid progressors among patients with ADPKD.

Associations of Urinary Collagen II Neoepitope C2C with Total Knee Replacement Outcomes: Is OA a Systemic Disease in Rapidly Progressive Cases?

The objective of this study was to investigate the dynamics of the urinary collagen type II C-terminal cleavage neoepitope (uC2C) before and after total knee replacement (TKR) in rapid knee OA progressors. C2C in the urine was measured by IBEX-uC2C assay in 86 patients (mean age: 59.9 years) with symptomatic knee OA (kOA) undergoing TKR, assessed before surgery and 3 and 12 months after. The patients’ condition was determined by self-assessment questionnaires, by lower limb performance tests, and by radiography. In the preoperative period, the uC2C level was significantly higher in females than in males, and was associated with the radiographic severity of kOA. A weak correlation between the C2C and knee pain was observed in the whole group and in males, but not in females. The individual dynamics of uC2C after TKR were heterogenic. In general, uC2C increased three months after TKR, but fell to the preoperative level after 12 months. A higher preoperative uC2C implied the tendency to diminish as a result of TKR, and vice versa. TKR did not stop the degradation of Coll2 in the tissues in the majority of cases. The pre-TKR uC2C predicts the postoperative uC2C level. The uC2C dynamic seems to be sex-specific, so it could be considered a prospective pre- and post-TKR biomarker for progressive kOA.

Single-Cell RNA-Seq Analysis of CD138-Depleted Bone Marrow Samples Reveals Genetic Alterations and Disease Progression Correlate with Tumor and Bone Marrow Immune Microenvironment in the Mmrf Commpass Study

Single-Cell RNA-Seq Analysis of CD138-Depleted Bone Marrow Samples Reveals Genetic Alterations and Disease Progression Correlate with Tumor and Bone Marrow Immune Microenvironment in the Mmrf Commpass Study