N-methyl-2-pyridone-5-carboxamide (N-Me-2PY) has potent anti-fibrotic and anti-inflammatory activity in a fibrotic kidney model: is it an old uremic toxin?

BACKGROUND: Uremic toxins accumulate in renal tissues and cells due to chronic kidney disease (CKD). Abnormalities in nicotinamide adenine dinucleotide (NAD +) metabolism lead to the progression of CKD. NAD + metabolites, such as N-methyl-2-pyridone-5-carboxamide (N-Me-2PY) and N-methyl-4-pyridone-5-carboxamide (N-Me-4PY), have been recognized as uremic toxins. However, no reports have validated whether they are actually harmful to the body. Therefore, we focused on the structural similarity of these metabolites to the anti-fibrotic drug pirfenidone and evaluated their effects on renal fibrosis. METHODS: Each NAD + metabolite was treated with TGFß1 to kidney fibroblasts or tubular epithelial cells, and quantitative RT-PCR and Western blot analysis were conducted. N-Me-2PY was orally administered to a ligated murine kidney fibrosis model (UUO) to evaluate its anti-fibrotic and toxic effects on the body. RESULTS: N-Me-2PY, N-Me-4PY, and nicotinamide N-oxide (NNO) inhibited TGFß1-induced fibrosis and inflammatory gene expression in kidney fibroblasts. N-Me-2PY strongly suppressed the expression of types I and III collagen, αSMA, and IL-6. N-Me-2PY also suppressed TGFß1-induced type I collagen and IL-6 expression in renal tubular epithelial cells. No toxic effect was observed with N-Me-2PY treatment, while attenuating renal fibrosis and tubular dilation in UUO mice. Suppression of various fibrosis- and inflammation-related genes was also observed. N-Me-2PY did not inhibit TGFß1-induced Smad3 phosphorylation but inhibited Akt phosphorylation, suggesting that N-Me-2PY exerts anti-fibrotic and anti-inflammatory effects through Akt inhibition, similar to pirfenidone. CONCLUSIONS: NAD + metabolites, such as N-Me-2PY, are not uremic toxins but are potential therapeutic agents that have anti-fibrotic effects in CKD.

Clinical evaluation of anterior nasal cavity swab specimens by a rapid antigen test using a GLINE-2019-nCoV Ag Kit to diagnose COVID-19.

The promising diagnostic performance of rapid antigen tests (RATs) using non-invasive anterior nasal (AN) swab specimens to diagnose COVID-19 has been reported. A large number of RATs are commercially available; however, the careful assessment of RATs is essential prior to their implementation in clinical practice. We evaluated the clinical performance of the GLINE-2019-nCoV Ag Kit as a RAT using AN swabs in a prospective, blinded study. Adult patients who visited outpatient departments and received SARS-CoV-2 tests between August 16 and September 8, 2022, were eligible for this study. Patients who were aged under 18 years and patients without appropriate specimens were excluded. Two sets of AN and nasopharyngeal (NP) swabs were collected from all patients. Each set of specimens was tested by the RAT and quantitative reverse-transcription polymerase chain reaction (RT-qPCR). Of the 138 recruited patients, 84 were positive and 54 were negative by RT-qPCR using NP swabs. The positive agreement rate between RT-qPCR using NP swabs and RAT using AN swabs was 78.6% (95% confidence interval [CI], 68.3%-86.8%), the negative agreement rate was 98.1% (95% CI, 90.1%-99.9%), and the overall agreement rate was 86.2% (95% CI, 79.3%-91.5%), with a κ coefficient of 0.73. The positive agreement rate in the early phase (≤3 days from symptom onset) was >80%, but this fell to 50% in the late phase (≥4 days). This study demonstrates that the GLINE-2019-nCoV Ag Kit using AN swabs has good clinical performance and might be a reliable alternative method for diagnosing COVID-19.

Evaluation of an immunochromatography-based rapid antigen test, Inspecter Kowa® SARS-CoV-2, using saliva specimens for the detection of SARS-CoV-2.

BACKGROUND: In the context of the coronavirus disease 2019 (COVID-19) pandemic, a rapid and reliable point-of-care test is an essential tool for controlling the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In particular, an immunochromatography test (ICT) that uses saliva specimens for rapid antigen detection not only reduces the risk of secondary infections but also reduces the burden on medical personnel. METHODS: The newly developed salivary antigen test kit "Inspecter Kowa® SARS-CoV-2" is an ICT to which saliva specimens can be directly applied. We evaluated its usefulness in comparison with reverse transcription quantitative PCR (RT-qPCR) and the Espline® SARS-CoV-2 Kit for the detection of SARS-CoV-2 using nasopharyngeal swab specimens. In this study, 140 patients with suspected symptomatic COVID-19 who visited our hospital were enrolled, and nasopharyngeal swab and saliva specimens were collected after they consented to participate in the study. RESULTS: Inspector Kowa SARS-CoV-2 was positive in 45 of 61 (73.8%) saliva that were positive by RT-qPCR and the Espline® SARS-CoV-2 Kit was also positive in 56 of 60 (93.3%) Np swabs that were positive by RT-qPCR. Good antigen detection was achieved by ICT with saliva and nasopharyngeal swab specimens when viral load was ≥105 copies/mL, whereas detection sensitivity was low when viral load was <105 copies/mL, especially in saliva specimens. CONCLUSION: This ICT for the detection of SARS-CoV-2 salivary antigen is an attractive tool that does not require specialized equipment and allows patients to perform the entire process from sample collection to self-diagnose and to reduce the burden on medical care during a pandemic.

Examination of colorectal cancer cases with metal allergy.

PURPOSE: To report our initiatives and treatment results for patients with colorectal cancer with metal allergy. METHODS: A total of 27 patients (2.6%) with a history of metal contact dermatitis were identified among 1027 patients who underwent curative resection of colorectal cancer from 2014 to 2020. The results of the patch test, perioperative results, and postoperative colonoscopy findings were also investigated. RESULTS: The patch test for metal allergens and staples was performed in 21 patients (77.8%), and 13 of them (61.9%) tested positive for at least one metal allergen. Ni (38.1%), Co (28.6%), and Pd (19.0%) showed higher positive rates than other metals, and 1 patient (4.8%) tested positive for staples. Stapled anastomosis/suturing was performed as planned in 15 of 27 patients. In 10 patients, the anastomosis method was changed from stapled to hand-sewn according to the no-patch test results (60%), positivity for multiple metals (20%), positivity for staples (10%), and surgeon's judgment (10%). No complications and abnormal colonoscopy findings were found to be associated with stapled anastomosis/suturing. CONCLUSION: The patch test is useful for selecting an optimal anastomosis method for patients with suspected metal allergy.

[A Case of Cecum Cancer with Lymph Node Metastasis and Invasion in the Superior Mesenteric Vein Treated with Combined SMV Resection and Reconstruction].

The patient was a 77-year-old woman. She visited her family doctor with a complaint of bloody stools, and was pointed out a Type 3 colon cancer in the cecum with a colonoscopy. In addition, an enlarged lymph node(#203)was found on the right side of the superior mesenteric vein(SMV). Laparoscopic surgery was initiated, and when the patient was moved to vascular processing, a firm adhesion of the lymph node(#203)was observed on the right side of the SMV. A small laparotomy was added, and a partial combined resection of the SMV was performed en bloc to complete the ileal resection. Histopathological findings showed T4b(transverse colon)N3M0, pStage Ⅲc, and metastatic lymph node(#203)showed evidence of invasion to the SMV. Adjuvant chemotherapy was administered, but lung metastases appeared 4 months and liver metastasis appeared 29 months after surgery. The patient was transferred to a different hospital for best supportive care(BSC)at 34 months after surgery.

[A Case Report of a Giant GIST Markedly Responsive to Neoadjuvant Chemotherapy with Imatinib Mesylate].

Male in his 50s complaining of abdominal pain was referred to our hospital. Abdominal CT scan showed a giant tumor which had diameter of approximately 50 mm in lower rectum. A biopsy specimen was positive for CD34 and c-kit. Based on these findings, it was diagnosed as gastrointestinal stromal tumor(GIST). We treated the patient with neoadjuvant therapy using imatinib mesylate(IM)to reduce the tumor size and to avoid the extensive surgery. The patient started to take IM at a daily dose of 400 mg. After 3 months, CT and MRI revealed that the tumor size decreased(40% reduction). We performed the robot assisted intersphincteric resection(ISR). Although it has been 28 months since the surgery, there are no obvious signs of recurrence. A patient diagnosed with giant GIST could avoid an extensive surgery due to neoadjuvant therapy with IM.

Concise Synthesis of Potassium Acyltrifluoroborates from Aldehydes through Copper(I)-Catalyzed Borylation/Oxidation.

Potassium acyltrifluoroborates (KATs) were prepared through copper(I)-catalyzed borylation of aldehydes and subsequent oxidation. This synthetic route is characterized by the wide range of aldehydes accessible, favorable step economy, mild reaction conditions, and tolerance of various functional groups, and it enables the facile generation of a range of KATs, for example, bearing halide, sulfide, acetal, or ester moieties. Moreover, this method was applied to the three-step synthesis of various α-amino acid analogues that bear a KAT moiety on the C-terminus by using naturally occurring amino acids as the starting material.

Self-perceptions from people with Down syndrome in Japan.

Self-perception of people with Down Syndrome (DS) was originally studied in the United States in 2011; this study indicated that 99% of people with DS are happy with their lives. In this study, we investigated self-perceptions of people with DS in Japan and compared the results to the previous study made in the United States. The participants (n = 300) were 12 years old or older and members of Japan Down Syndrome Society (JDS). The questionnaire was collected between 30 October 2015 and 26 November 2015. Of 96(32%) responses, 76 (97%) agreed they are happy with their lives. We found that most people with DS in Japan also feel positive about themselves and their lives. Along with the start of Non-Invasive Prenatal Testing in Japan, DS draws an attention from Japanese people because maternal age has been increasing. This has resulted in the growth of the number of prenatal tests marketed in Japan. Therefore, we expect our results to be relevant to genetic counseling for the couples considering prenatal tests or parents raising their children with DS so that they have a clearer image about life with DS and can better visualize their life plans.

Repeated laparoscopic resection of extra-regional lymph node metastasis after laparoscopic radical resection for rectal cancer.

Here, we report a case of repeated laparoscopic resection of extra-regional lymph node metastases in a patient after laparoscopic surgery for rectal cancer. A 72-year-old woman was diagnosed with upper rectal cancer and underwent laparoscopic low anterior resection and D3 dissection. The pathological stage was considered as T3, N2b, M0, Stage IIIC. Six months after the operation, positron emission tomography-computed tomography (PET-CT) showed fluorodeoxyglucose (FDG) accumulation in the infra-renal para-aortic lymph nodes (PALNs). Systemic chemotherapy was administered; however, chemotherapy was discontinued due to hemoptysis related to her pulmonary disease. Therefore, we performed laparoscopic PALN resection. Pathologically, one lymph node was diagnosed with a metastasis. Three months after the second operation, PET-CT identified FDG accumulation in the left lateral pelvic lymph nodes (LPLNs) and a PALN. Laparoscopic LPLN dissection and PALN resection through minilaparotomy were performed. Pathologically, lymph node metastases were diagnosed in both fields. Sixteen months after the 3rd operation, there is no recurrence.

A case of total laparoscopic sigmoidectomy involving the use of needle forceps and transanal specimen extraction for sigmoid colon cancer.

A 76-year-old male underwent endoscopic mucosal resection for a stage T1 tumour of the sigmoid colon. We performed laparoscopic sigmoidectomy through 5 ports using needlescopic instruments. The resected specimen was extracted from the abdominal cavity transanally. After attaching an anvil to the sigmoidal stump, the rectal stump was reclosed using an endoscopic linear stapler, and then, colorectal anastomosis was conducted using the double stapling technique. Performing transanal specimen extraction using needlescopic forceps improves aesthetic outcomes and reduces post-operative pain and the risk of abdominal incisional hernias. This method is an easy to introduce a form of reduced-port surgery because of its feasibility and conventional port arrangement. Hence, we consider that it is an option for minimally invasive surgery.

Synthesis of Acylborons by Ozonolysis of Alkenylboronates: Preparation of an Enantioenriched Amino Acid Acylboronate.

A concise synthesis of acylborons was achieved by ozonolysis of alkenyl MIDA (N-methyliminodiacetic acid) boronates. This reaction exhibits excellent functional-group tolerance and is applicable to various acyl MIDA boronates and potassium acyltrifluroborates (KATs) which could not be synthesized by previous methods. In addition, α-amino acylborons, which would be essential for peptide ligations, were prepared for the first time. The acylboron of l-alanine was obtained in high enantiopurity and found to be configurationally stable. Oligopeptide synthesis between the α-amino KATs and amino acid in dilute aqueous media was studied.

Aberrant assembly of RNA recognition motif 1 links to pathogenic conversion of TAR DNA-binding protein of 43 kDa (TDP-43).

Aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is a pathological signature of amyotrophic lateral sclerosis (ALS). Although accumulating evidence suggests the involvement of RNA recognition motifs (RRMs) in TDP-43 proteinopathy, it remains unclear how native TDP-43 is converted to pathogenic forms. To elucidate the role of homeostasis of RRM1 structure in ALS pathogenesis, conformations of RRM1 under high pressure were monitored by NMR. We first found that RRM1 was prone to aggregation and had three regions showing stable chemical shifts during misfolding. Moreover, mass spectrometric analysis of aggregated RRM1 revealed that one of the regions was located on protease-resistant ß-strands containing two cysteines (Cys-173 and Cys-175), indicating that this region served as a core assembly interface in RRM1 aggregation. Although a fraction of RRM1 aggregates comprised disulfide-bonded oligomers, the substitution of cysteine(s) to serine(s) (C/S) resulted in unexpected acceleration of amyloid fibrils of RRM1 and disulfide-independent aggregate formation of full-length TDP-43. Notably, TDP-43 aggregates with RRM1-C/S required the C terminus, and replicated cytopathologies of ALS, including mislocalization, impaired RNA splicing, ubiquitination, phosphorylation, and motor neuron toxicity. Furthermore, RRM1-C/S accentuated inclusions of familial ALS-linked TDP-43 mutants in the C terminus. The relevance of RRM1-C/S-induced TDP-43 aggregates in ALS pathogenesis was verified by immunolabeling of inclusions of ALS patients and cultured cells overexpressing the RRM1-C/S TDP-43 with antibody targeting misfolding-relevant regions. Our results indicate that cysteines in RRM1 crucially govern the conformation of TDP-43, and aberrant self-assembly of RRM1 at amyloidogenic regions contributes to pathogenic conversion of TDP-43 in ALS.

Laparoscopic intersphincteric resection using needlescopic instruments.

Intersphincteric resection (ISR) is a procedure designed to preserve anal function in cases with very low rectal cancer. We report our clinical experience with laparoscopic ISR (Lap ISR) performed using needlescopic instruments. First, a camera port is created at the umbilicus. Two 5-mm ports are then inserted at the right upper and lower quadrants. Two needlescopic forceps (Endo-Relief(™) Hope Denshi Co., Chiba, Japan) are inserted at the left upper and lower quadrants. We then perform the following procedures; ligation of the inferior mesenteric artery and vein, total mesorectal excision and dissection of the intersphincteric space. After the transanal intersphincteric dissection, the specimen is extracted through the anus and a hand -sewn coloanal anastomosis is performed. The covering ileostomy is finally created at the right upper port. We performed Lap ISR using needlescopic forceps in two patients with very low rectal cancer. In both cases, we were able to perform this procedure without insertion of an additional port or to change the needlescopic forceps to conventional 5-mm forceps. Lap ISR with needlescopic instruments is a feasible procedure for minimally invasive surgery.

Subtotal Second Toe Transfer for Finger Reconstruction after Malignant Fibroblastic Tumor Resection.

The transposition of an adjacent finger following the loss of a finger due to a malignant tumor resection improves hand function. However, patients may not accept the resulting appearance of a three-finger hand. A 28-year-old male with a malignant fibroblastic tumor at the base of the ring finger underwent resection of the tumor, excising the phalanx and a portion of the metacarpal. He refused a ray amputation and subsequent fifth-finger transposition. Therefore, we reconstructed the defect with a long-vascularized subtotal second toe from the metacarpal neck to the middle phalanx base of the fourth finger. There was no tumor recurrence, and the patient was highly satisfied with hand function and cosmetic appearance at 3 years of follow-up.

Mechanochemical protocol facilitates the generation of arylmanganese nucleophiles from unactivated manganese metal.

The direct synthesis of organomanganese reagents from organic halides and manganese metal remains a challenge. Current solution-based approaches require the preparation of activated manganese (Rieke manganese) or the use of multiple metal additives to promote the insertion of manganese metal into a carbon-halogen bond. Here, we show that a mechanochemical ball-milling protocol facilitates the generation of various arylmanganese nucleophiles from aryl halides and commercially available, unactivated manganese metal without the need for complicated pre-activation processes and metal additives. These manganese-based carbon nucleophiles can be used directly for one-pot addition reactions with various electrophiles and palladium-catalyzed cross-coupling reactions under bulk-solvent-free mechanochemical conditions. Importantly, all experimental operations can be conducted under atmospheric conditions.

Evaluation of the Safety and Efficacy of Modified Laparoscopic Suture Rectopexy for Rectal Prolapse.

Objectives: There are many surgical options for the treatment of rectal prolapse. To date, the efficacy of mesh-free laparoscopic suture rectopexy remains unclear due to the limited number of reports. This study aimed to evaluate the safety and efficacy of laparoscopic suture rectopexy. Methods: This observational cohort study is a retrospective cross-sectional analysis of a continuously maintained database. All patients underwent laparoscopic suture rectopexy for rectal prolapse between April 2012 and March 2018. The primary outcomes measured were recurrence rates and complications of laparoscopic suture rectopexy. Results: A total of 268 patients (29 male and 239 female) underwent laparoscopic suture rectopexy. Their mean age was 77 (19-95) years, and the mean prolapse length was 6.4 (3.5-20) cm. One patient suffered an intraabdominal abscess. Spondylitis developed in another patient following surgery. The median follow-up period was 45 (12-82) months. A total of 22 patients (8.2%) developed recurrence. The average time to recurrence was 15.6 (1-44) months. Multivariate analysis revealed a significant correlation between recurrence and prolapse length >7.0 cm (OR: 1.26, 95% CI: 1.38-1.42, P < 0.01). Conclusions: Laparoscopic suture rectopexy for complete rectal prolapse is a minimally invasive and safe procedure that may lead to lower recurrence rates.

Mean annual intradialytic blood pressure decline and cardiovascular events in Japanese patients on maintenance hemodialysis.

An intradialytic systolic blood pressure (SBP) decline, which defines intradialytic hypotension, may be associated with higher all-cause mortality. However, in Japanese patients on hemodialysis (HD), the association between intradialytic SBP decline and patient outcomes is unclear. This retrospective cohort study included 307 Japanese patients undergoing HD over 1 year in three dialysis clinics and evaluated the association between the mean annual intradialytic SBP decline (predialysis SBP-nadir intradialytic SBP) and clinical outcomes, including major adverse cardiovascular events (MACEs; cardiovascular death, nonfatal myocardial infarction or unstable angina, stroke, heart failure, and other severe cardiovascular events requiring hospitalization) by following up for 2 years. The mean annual intradialytic SBP decline was 24.2 (25-75th percentile, 18.3-35.0) mmHg. In the model fully adjusted for intradialytic SBP decline tertile group (T1, <20.4 mmHg; T2, 20.4 to <29.9 mmHg; T3, ≥29.9 mmHg), predialysis SBP, age, sex, HD vintage, Charlson comorbidity index, ultrafiltration rate, use of renin-angiotensin system inhibitors, corrected calcium, phosphorus, human atrial natriuretic peptide, geriatric nutritional risk index, normalized protein catabolism rate, C-reactive protein, hemoglobin, and use of pressor agents, Cox regression analyses showed that the hazard ratio (HR) was significantly higher for T3 than for T1 for MACEs (HR, 2.38; 95% confidence interval 1.12-5.09) and all-cause hospitalization (HR, 1.68; 95% confidence interval 1.03-2.74). Therefore, in Japanese patients on HD, a greater intradialytic SBP decline was associated with worse clinical outcomes. Further studies are warranted to investigate whether interventions to attenuate the intradialytic SBP decline will improve the prognosis of Japanese patients on HD.

Seasonal variation in predialysis systolic blood pressure and cardiovascular events in patients on maintenance hemodialysis.

Predialysis systolic blood pressure (SBP) in patients on hemodialysis (HD) consistently followed a seasonal pattern, reaching a peak in winter and nadir in summer, similar to blood pressure in the general population. However, the relationship between seasonal variations in predialysis SBP and clinical outcomes is still under-investigated in Japanese patients on HD. This retrospective cohort study included 307 Japanese patients undergoing HD for >1 year in three dialysis clinics and evaluated the association between the standard deviation (SD) of predialysis SBP and clinical outcomes, including major adverse cardiovascular events (MACEs; cardiovascular death, nonfatal myocardial infarction or unstable angina, stroke, heart failure, and other severe cardiovascular events requiring hospitalization) with 2.5 years follow-up. The SD of predialysis SBP was 8.2 (6.4-10.9) mmHg. In the model fully adjusted for the SD of predialysis SBP, predialysis SBP, age, sex, HD vintage, Charlson comorbidity index, ultrafiltration rate, renin-angiotensin system inhibitors, corrected calcium, phosphorus, human atrial natriuretic peptide, C-reactive protein, albumin, hemoglobin, body mass index, normalized protein catabolism rate, and intradialytic SBP decline, Cox regression analyses showed that a higher SD of predialysis SBP (per 10 mmHg) was significantly associated with increased MACE risk (hazard ratio [HR], 1.89; 95% confidence interval [95% CI], 1.07-3.36) and all-cause hospitalization (HR, 1.57; 95% CI, 1.07-2.30). Therefore, greater seasonal variations in predialysis SBP were associated with worse clinical outcomes, including MACEs and all-cause hospitalization. Whether interventions to reduce seasonal variations in predialysis SBP will improve the prognosis of Japanese patients on HD must be investigated further.

Comparison of the effects of angiotensin receptor-neprilysin inhibitors and thiazide diuretic/renin-angiotensin system inhibitor combination therapy in hypertensive patients: a retrospective cohort study.

Angiotensin receptor-neprilysin inhibitors (ARNIs) have been approved as antihypertensive agents in Japan, and thiazide diuretics (TZDs) are widely used concomitantly with renin-angiotensin system inhibitors (RASIs) for hypertension. This retrospective study included patients with hypertension who switched from RASI to ARNI therapy (ARNI group) and those who were prescribed TZDs with RASIs (TZD/RASI group). Drug-related changes in the estimated glomerular filtration rate (eGFR), blood pressure (BP), body weight (BW), serum electrolytes, uric acid (UA), and triglyceride levels were compared between the two groups. Overall, 70 participants (31 and 39 in the ARNI and TZD/RASI groups, respectively) were enrolled and observed for a median of 2 months. According to linear mixed models, compared with the TZD/RASI group, the ARNI group exhibited a significant change in mean eGFR of 3.71 mL/min/1.73 m2 [95% confidence interval (CI), 0.57-6.84; P = 0.02] from the time of switching drug to the next outpatient visit. Further, compared with the TZD/RASI group, the ARNI group exhibited significant changes in mean serum UA (-1.27; 95% CI, -1.66 to -0.88), sodium (1.22; 95% CI, 0.12 to -2.32), chloride (2.14; 95% CI, 0.75-3.52), and triglyceride (-52.1; 95% CI, -100.9 to -3.29) levels. Conversely, serum potassium levels, BW, and systolic and diastolic BP did not differ significantly between the two groups (P = 0.69, 0.44, 0.49, and 0.66, respectively). Compared with the combination therapy of TZD and RASI, ARNI therapy causes less renal dysfunction, hyperuricemia, and hypertriglyceridemia with fewer electrolyte abnormalities and no significant difference in antihypertensive effects.

Correlation between acylcarnitine/free carnitine ratio and cardiopulmonary exercise test parameters in patients with incident dialysis.

Objective: Diminished physical capacity is common and progressive in patients undergoing dialysis, who are also prone to deficiency in carnitine, which plays a pivotal role in maintaining skeletal muscle and cardiac function. The present study aimed to evaluate the association of carnitine profile with exercise parameters in patients with incident dialysis. Design and Methods: This was a single-center cross-sectional study including 87 consecutive patients aged 20-90 years who were initiated on dialysis in Keio University Hospital between December 2019 and December 2022 and fulfilled the eligibility criteria. Exercise parameters were evaluated via cardiopulmonary testing (CPX) using the electronically braked STRENGTH ERGO 8 ergometer, whereas the carnitine profile was assessed by determining serum free carnitine (FC), acylcarnitine (AC) levels and AC/FC ratio. Results: The mean cohort age was 62.1 ± 15.2 years, with male and hemodialysis predominance (70% and 73%, respectively). AC/FC was 0.46 ± 0.15, and CPX revealed peak oxygen consumption (VO2) of 13.9 ± 3.7 (mL/kg/min) with percent-predicted peak VO2 of 53.6% ± 14.7% and minute ventilation (VE)/carbon dioxide output (VCO2) slope of 35.1 ± 8.0. Fully-adjusted multivariate linear regression analysis showed that AC/FC was significantly associated with decreased peak VO2 (ß, -5.43 [95% confidence interval (CI), -10.15 to -0.70]) and percent-predicted peak VO2 (ß, -19.98 [95% CI, -38.43 to -1.52]) and with increased VE/VCO2 slope (ß, 13.76 [95% CI, 3.78-23.75]); FC and AC did not exhibit similar associations with these parameters. Moreover, only AC/FC was associated with a decreased peak work rate (WR), percent-predicted WR, anaerobic threshold, delta VO2/delta WR, and chronotropic index. Conclusion: In patients on incident dialysis, exercise parameters, including those related to both skeletal muscle and cardiac function, were strongly associated with AC/FC, a marker of carnitine deficiency indicating altered fatty acid metabolism. Further studies are warranted to determine whether carnitine supplementation can improve exercise capacity in patients on incident dialysis.