Oral Colchicine and Low-Dose Aspirin Combination Therapy for Non-elderly, Non-severe, Early Time From Onset, Adult Outpatients with Coronavirus Disease 2019 (COVID-19) during "The Fifth Pandemic Wave" in Japan.

BACKGROUND: Treatment with antiviral drugs for non-severe, early time from onset, adult outpatients with Coronavirus Disease 2019 (COVID-19) had not been established in 2021. However, some new variants of SARS-CoV-2 had caused rapid exacerbation and hospitalization among non-elderly outpatients with COVID-19, contributing to widespread crises within healthcare systems. METHODS: From July to October 2021, we urgently assessed a therapeutic program using oral colchicine (1.0 mg loading dose, followed approximately half a day later by 0.5 mg twice daily for 5 days, and then 0.5 mg once daily for 4 days) and low-dose aspirin (100 mg once daily for 10 days), for non-elderly, non-severe, early time from onset, adult outpatients with COVID-19. To verify its effectiveness, we set loxoprofen as a control arm, and com parison of these two arms was performed. The primary outcomes were hospitalization, criticality, and death rates. RESULTS: Thirty-eight patients (23 receiving colchicine and low-dose aspirin [CA]; 15 receiving loxoprofen [LO]) were evaluated. Hospitalization rate was lower in the CA group (1/23; 4.3%) than in the LO group (2/15; 13.3%); however, no significant difference was found between the two groups (p=0.34). No critical cases, deaths, or severe adverse events were found in either group. CONCLUSIONS: Our CA regimen did not show superiority over LO treatment. However, our clinical experience should be recorded as part of community health care activities carried out in Kurume City against the unprece dented COVID-19 pandemic.

Decreased serum carnitine is independently correlated with increased tissue accumulation levels of advanced glycation end products in haemodialysis patients.

AIM: There is accumulating evidence that advanced glycation end products (AGE) play a role in cardiovascular disease (CVD) in patients with haemodialysis (HD). Carnitine deficiency is frequently observed in HD patients, which may also contribute to CVD. In this study, we examined whether carnitine deficiency was independently associated with increased tissue accumulation levels of AGE in HD patients. METHODS: One hundred and twenty-nine HD patients underwent determinations of blood chemistries including serum level of carnitine. Tissue AGE levels were evaluated by measuring skin autofluorescence with an AGE-reader. RESULTS: Serum carnitine levels were significantly lower, while skin AGE levels were significantly higher in HD patients compared with healthy controls (P < 0.001). In univariate analysis, ß(2)-microglobulin (ß(2)-MG) and carnitine (inversely) were correlated with skin AGE levels. Multiple stepwise regression analysis revealed that carnitine levels were one of the independent determinants of skin AGE levels (P = 0.024). When ß(2)-MG-adjusted skin AGE levels were stratified by serum carnitine levels, a statistical significance and dose-response relationship were observed (P = 0.043). Furthermore, skin AGE levels were one of the independent determinants of serum carnitine levels as well (P = 0.012). CONCLUSION: The present study demonstrated that decreased carnitine levels were independently associated with increased skin AGE levels in HD patients. Since carnitine is reported to inhibit the formation of AGE in vitro, our study suggests that supplementation of carnitine may be a therapeutic target for preventing the accumulation of tissue AGE and subsequently reducing the risk of CVD in HD patients.

[Clinical evaluation of tonsillectomy with modified high-dose intravenous methylprednisolone therapy in patients with IgA nephropathy].

Immunoglobulin A nephropathy (IgAN) is now recognized as the most common form of primary glomerulonephritis worldwide and is the major cause of end-stage renal disease. As reported, the renal survival rate is 61% at 20 years and the renal prognosis of this disease is relatively poor on long-term observation, hence various protocols have been attempted to control this disease. At Iizuka Hospital, a prospective study of tonsillectomy with methylprednisolone pulse therapy was performed for the treatment of patients with IgA nephropathy from August 2002. We reviewed the clinical efficacy of our protocol. From August 2002 to July 2006, 31 patients whose IgA nephropathy was demonstrated by percutaneous renal biopsy were administered our regimen. In our study, 12 patients had an observation period of more than 24 months. Our protocol consisted of tonsillectomy with one course of methylprednisolone pulse therapy. Methylprednisolone at the daily dose of 1,000 mg for 3 consecutive days followed by oral steroid at the daily dose of 20 mg, was gradually tapered, and discontinued one year later. All of the patients were administered angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with favorable control of hypertension. The mean observation period for the 12 patients with IgA nephropathy was 37.4 months. The mean age at renal biopsy was 34.8 +/- 12.2 years. The male-female ratio was 3:9. At the renal biopsy in our hospital, mean creatinine value was 0.95 +/- 0.38 mg/dL, mean creatinine clearance was 92.1 +/- 34.9 mL/min, and the mean urinary protein and urinary creatinine ratio was 3.52 +/- 4.36. After 24 months, mean creatinine value was 1.03 +/- 0.59 mg/dL, mean creatinine clearance was 91.2 +/- 42.3 mL/min, and the mean urinary protein and urinary creatinine ratio was 0.83 +/- 0.98. Urinary protein and urine occult blood became negative in 66.7% of patients, and the urinary remission rate was 58.3%. On our protocol, mean length of the hospital stay was 11.4 +/- 4.7 days. Our prospective study showed that tonsillectomy with one course of methylprednisolone pulse therapy in IgA nephropathy appears to be beneficial for urinary remission and contributes to a short hospital stay.

Dialysate vascular endothelial growth factor is an independent determinant of serum albumin levels and predicts future withdrawal from peritoneal dialysis in uremic patients.

Peritoneal protein loss due to high peritoneal permeability may contribute to hypoalbuminemia and early withdrawal from peritoneal dialysis (PD) therapy in end stage renal disease (ESRD) patients. We have found that pigment epithelium-derived factor (PEDF) has anti-vasopermeability properties both in cell culture and animal models by counteracting the biological actions of vascular endothelial growth factor (VEGF). However, it remains unknown which clinical variables, including dialysate VEGF and PEDF, are associated with decreased serum albumin levels and could predict early withdrawal from the PD in ESRD patients. We address these issues. Twenty-seven ESRD patients undergoing PD were enrolled. Clinical variables were measured at 6 months after commencing PD. We examined the independent correlates of serum albumin in PD patients and then prospectively investigated the predictors of withdrawal from the PD therapy over 4 years. Dialysate VEGF was associated with peritoneal solute transport rate (P = 0.002), serum albumin (inversely, P < 0.001) and dialysate PEDF levels (P < 0.001). In multiple stepwise regression analysis, age (P = 0.002) and dialysate VEGF levels (P < 0.001) were independent determinants of serum albumin levels. High VEGF (>27 pg/mL), low serum albumin (≤ 3.31 g/dL) and low hemoglobin (≤ 11.2 g/dL) were correlated with withdrawal from the PD therapy during the 4 years. The odds ratio of dialysate VEGF for early withdrawal from the PD was 6.310 (P = 0.035). The present study demonstrated that increased dialysate VEGF was associated with decreased serum albumin and early withdrawal from the PD therapy. Inhibition of peritoneal VEGF production may be a therapeutic target in PD patients.

Potential inhibitory effects of L-carnitine supplementation on tissue advanced glycation end products in patients with hemodialysis.

BACKGROUND AND AIMS: Advanced glycation end products (AGEs) contribute to cardiovascular disease in patients with hemodialysis (HD). We have recently found that carnitine levels are inversely associated with skin AGE levels in HD patients. We examined whether L-carnitine supplementation reduced skin AGE levels in HD patients with carnitine deficiency. METHODS: This was a single-center study. One hundred and two HD patients (total carnitine levels <50 µmol/L) were enrolled and randomized to either oral administration of L-carnitine (900 mg/day) (n=51) or control (n=51). After 6 months, metabolic and inflammatory variables, including serum levels of carnitine, were measured. Skin AGE levels were determined by evaluating skin auto-fluorescence with an AGE-reader. RESULTS: There were no significant differences of clinical variables at baseline between the control and L-carnitine therapy group. Thirty-two patients did not complete the assessment or treatment of the study. Oral L-carnitine supplementation for 6 months significantly increased low-density lipoprotein cholesterol (LDL-C), triglycerides, total, free, and acyl carnitine levels, while it decreased alanine transaminase, acyl/free carnitine ratio, ß2-microglobulin, and skin AGE values. Change in total carnitine values from baseline (Δtotal carnitine) and Δfree carnitine were inversely associated with Δskin AGE levels in L-carnitine-treated patients (p=0.036 and p=0.016, respectively). In multiple regression analysis, Δfree carnitine was a sole independent determinant of Δskin AGEs (R²=0.178). CONCLUSIONS: The present study demonstrated that oral L-carnitine supplementation significantly decreased skin AGE levels in HD patients with carnitine deficiency. These observations suggest that supplementation of L-carnitine might be a novel therapeutic strategy for preventing the accumulation of tissue AGEs in carnitine-deficient patients with HD.

Evidence for a positive association between serum carnitine and free testosterone levels in uremic men with hemodialysis.

BACKGROUND AND AIMS: Low free testosterone levels are associated with sexual dysfunction and an increased risk of cardiovascular disease in male hemodialysis patients. Carnitine deficiency is frequently observed in hemodialysis patients as well. However, the relationship between carnitine and testosterone levels remains unknown. In this study, we examined whether carnitine deficiency was independently associated with low free testosterone levels in male hemodialysis patients. METHODS: Nineteen male hemodialysis patients underwent determinations of blood chemistries, including serum levels of free testosterone, carnitine, and pentosidine, one of the well-characterized advanced glycation end products. RESULTS: Mean free testosterone levels in hemodialysis patients were significantly lower than those in healthy controls (4.67±2.69 vs. 9.50±3.67 pg/mL, p<0.001). Univariate analysis revealed that carnitine (p=0.023), pentosidine (inversely, p=0.027), blood glucose (inversely, p=0.032), creatinine (p=0.026) levels, and statin use (inversely, p=0.034) were correlated with free testosterone values. Multiple stepwise regression analysis revealed that carnitine (p=0.001) and statin use (inversely, p=0.002) were the independent determinants of age-adjusted free testosterone levels in hemodialysis patients (r² =0.612). CONCLUSIONS: The present study gives the first evidence that decreased carnitine levels were independently associated with low free testosterone values in male hemodialysis patients. Our study suggests that decreased carnitine levels may be a novel therapeutic target for uremic men with hemodialysis.

Effects of switching from calcium carbonate to lanthanum carbonate on bone mineral metabolism in hemodialysis patients.

Phosphate binders are useful for the treatment of hyperphosphatemia in hemodialysis (HD) patients. This study was performed to examine the effects of switching from calcium carbonate (CC) to lanthanum carbonate (LC) on bone mineral metabolism and inflammatory markers in HD patients. We conducted 29 stable HD patients receiving CC, which was replaced by LC and followed-up for 12 weeks. Patients underwent determinants of blood chemistries such as serum calcium (Ca), phosphorus, parathyroid hormone (PTH) and vitamin D status, and interleukin-6 (IL-6) mRNA levels in whole blood cells were evaluated by real-time PCR just before and after the treatment with LC. Corrected Ca [corrected] levels were significantly reduced, but serum phosphorus levels (P levels) were unchanged after LC treatment. Switching to LC increased whole-PTH, osteocalcin, 1,25(OH)(2) D(3) levels and 1,25(OH)(2) D(3)/25(OH)D(3) ratio. 1,25(OH)(2) D(3)/25(OH)D(3) ratio was negatively correlated with HD duration. Furthermore, whole blood cell IL-6 mRNA levels were significantly reduced by LC treatment. We provided that the switching from CC to LC improved Ca overload and ameliorated vitamin D and inflammatory status in HD patients. These observations suggest that LC may play a protective role for the progression of atherosclerosis and vascular calcification in these patients.