Risk stratification for infection during immunosuppressive therapy in patients with lupus nephritis: A nested case-control study.

BACKGROUND: The current prediction models for the risk of infection during immunosuppressive treatment for lupus nephritis (LN) lack a prediction time window and have poor pertinence. This study aimed to develop a risk stratification to predict infection during immunosuppressive therapy in patients with LN. METHODS: This retrospective nested case-control study collected patients with LN treated with immunosuppressive therapy between 2014 and 2022 in the Nephrology ward in Huashan Hospital affiliated to Fudan University and Huashan Hospital Baoshan Branch. Cases were defined as patients who experienced infection during the follow-up period; patients were eligible as controls if they did not have infection during the follow-up period. RESULTS: There were 53 patients with infection by CTCAE V5.0 grade ≥2. According to the 1:3 nested matching, the 53 patients with infection were matched with 159 controls. In the multivariable logistic regression model, the change rate of fibrinogen (OR = 0.97, 95% CI: 0.94-0.99, p = 0.008), leukopenia (OR = 8.68, 95% CI: 1.16-301.72, p = 0.039), and reduced albumin (OR = 6.25, 95% CI: 1.38-28.24, p = 0.017) were independently associated with infection. The AUC of the ROC curve in the validation set of the multivariable logistic regression model in the internal random sampling was 0.864. The scores range from -2 to 10. The infection risk stratification ranges from 2.8% at score -2 to 97.5% at score 10. CONCLUSION: A risk stratification was built to predict the risk of infection in patients with LN undergoing immunosuppressive therapy.

Association of frequent intradialytic hypotension with the clinical outcomes of patients on hemodialysis: a prospective cohort study.

Intradialytic hypotension (IDH) is a common complication of hemodialysis (HD), but there is no consensus on its definition. In 2015, Flythe proposed a definition of IDH (Definition 1 in this study): nadir systolic blood pressure (SBP) <90 mmHg during hemodialysis for patients with pre-dialysis SBP <159 mmHg, and nadir SBP <100 mmHg during hemodialysis for patients with pre-dialysis SBP ≥160 mmHg. This prospective observational cohort study investigated the association of frequent IDH based on Definition 1 with clinical outcomes and compared Definition 1 with a commonly used definition (nadir SBP <90 mmHg during hemodialysis, Definition 2). The incidence of IDH was observed over a 3-month exposure assessment period. Patients with IDH events ≥30% were classified as 'frequent IDH'; the others were 'infrequent IDH'. All-cause mortality, cardiovascular mortality, and all-cause hospitalization events were followed up for 36 months. This study enrolled 163 HD patients. The incidence of IDH was 11.1% according to Definition 1 and 10.5% according to Definition 2. The Kaplan-Meier curves showed that frequent IDH patients had higher risks of all-cause mortality (p = 0.009, Definition 1; p = 0.002, Definition 2) and cardiovascular mortality (p = 0.021, Definition 1). Multivariable Cox regression analysis indicated that frequent IDH was independently associated with a higher risk of all-cause mortality (Model 1: HR = 2.553, 95%CI 1.334-4.886, p = 0.005; Model 2: HR = 2.406, 95%CI 1.253-4.621, p = 0.008). In conclusion, HD patients classified as frequent IDH are at a greater risk of all-cause mortality. This highlights the significance of acknowledging and proactively managing frequent IDH within the HD patients.

Impact of frequent intradialytic hypotension on quality of life in patients undergoing hemodialysis.

BACKGROUND: Intradialytic hypotension (IDH) is frequently accompanied by symptoms of nausea, dizziness, fatigue, muscle spasm, and arrhythmia, which can adversely impact the daily lives of patients who undergo hemodialysis and may lead to decreased quality of life (QoL). This study employed the KDQOL™-36 scale to evaluate the impact of frequent IDH, based on the definition determined by predialysis blood pressure (BP) and nadir systolic blood pressure (SBP) thresholds, on the QoL of patients. METHODS: This is a single center retrospective cohort study involving 160 hemodialysis patients. We enrolled adult patients with uremia who received routine hemodialysis (4 h/time, 3 times/week) from October 1, 2019, to September 30, 2021. Frequent IDH was defined as an absolute nadir SBP < 90 mmHg occurring in no less than 30% of hemodialysis sessions when predialysis SBP < 159 mmHg (or < 100 mmHg when predialysis BP ≥ 160 mmHg).The differences between patients with and without frequent IDH were compared using the independent t test, Kruskal‒Wallis test, or chi-square test. The primary visit was at month 36, and the remaining visits were exploratory outcomes. RESULTS: Compared to patients with infrequent IDH at baseline, those with frequent IDH had significantly lower scores on the symptoms and discomfort of kidney disease dimension at all follow-up points (P < 0.05). The symptoms and discomfort of kidney disease dimension were worse in patients with frequent IDH. Those with frequent IDH had a significantly poorer QoL regarding the dimensions of symptoms and discomfort of kidney disease and the impact of kidney disease on life. CONCLUSIONS: The findings of the study suggest an association between frequent IDH and QoL dimensions of symptoms and discomfort of kidney disease and the impact of kidney disease on life dimension under the definition of frequent IDH.

Pharmacokinetics of benapenem for injection in subjects with mild to moderate renal impairment.

OBJECTIVE: This study evaluated the pharmacokinetic (PK) characteristics of benapenem in subjects with mild to moderate renal impairment to provide a reference for benapenem dosing regimens in this patient population. METHODS: Eighteen subjects were enrolled in this study. Each subject received a single dose of benapenem intravenously (1.0 g in 100 ml of 0.9% saline) followed by blood and urine collection to measure the concentrations of benapenem and its major metabolite. PK analysis was performed to evaluate the effect of varying degrees of renal impairment on the PK characteristics of benapenem. The safety of benapenem was also evaluated. RESULTS: In subjects with normal renal function, mild renal impairment, and moderate renal impairment, the maximum plasma benapenem concentrations were 163 ± 6.58 mg/L, 138 ± 17.4 mg/L, and 134 ± 0.11 mg/L, respectively (15.3% and 17.8% lower in subjects with mild and moderate renal impairment, respectively, than in subjects with normal renal function). The areas under the plasma concentration-time curve (AUC0-inf) were 1153.67 ± 143.2 mg·h/L, 1129.17 ± 241.41 mg·h/L, and 1316.46 ± 229.83 mg·h/L, respectively (P > 0.05); the cumulative urinary excretion rates at 72 h after dosing were 52.61 ± 8.58%, 39.42 ± 8.35%, and 29.84 ± 9.15%, respectively; and the metabolic ratio (AUC0-inf_KBP-3331/AUC0-inf_benapenem) were 3.96 ± 0.35%, 5.56 ± 0.82%, and 8.24 ± 0.85%, respectively. No drug-related adverse events (AEs), serious AEs, or AEs leading to withdrawal occurred in this study. CONCLUSION: No adjustment to benapenem dosing is needed in patients with mild to moderate renal impairment. CLINICAL TRIAL REGISTRATION: Drug clinical trial registration and information publicity platform: http://www.chinadrugtrials.org.cn/index.html . REGISTRATION NUMBER: CTR20190760.

Nemonoxacin dosage adjustment in patients with severe renal impairment based on population pharmacokinetic and pharmacodynamic analysis.

AIMS: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic (PPK)/pharmacodynamic analysis. METHODS: The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of a 0.5-g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 72 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment and the cumulative fraction of response against Streptococcus pneumoniae and Staphylococcus aureus was calculated by Monte Carlo simulation. RESULTS: The data best fitted a 2-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L) and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4 ± 6.5% in severe renal impairment patients and 66.1 ± 16.8% in healthy controls. PPK/pharmacodynamic modelling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g every 48 hours (q48h) was the optimal dosing regimen in severe renal impairment patients, evidenced by higher probability of target attainment (92.7%) and cumulative fraction of response (>99%) at nemonoxacin minimum inhibitory concentration ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if minimum inhibitory concentration = 1 mg/L. CONCLUSION: An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.

PLA2R1 and HLA-DQA1 gene variations in idiopathic membranous nephropathy in South China.

INTRODUCTION: Associations of variations in PLA2R1 and HLA-DQA1 genes with susceptibility to idiopathic membranous nephropathy (IMN) have been well documented. Association with spontaneous remission, however, is poorly defined in the Chinese Han population. METHODS: A Chinese cohort of 117 IMN patients and 138 healthy controls were recruited between July 2009 and November 2019. Case-control studies for single-nucleotide polymorphisms (SNPs) within HLA-DQA1 (rs2187668) and PLA2R1 (rs35771982, rs4664308, rs3749117, rs3749119) genes were performed. The contributions of these polymorphisms to predict susceptibility, titre of autoantibodies against the M-type phospholipase A2 receptor (anti-PLA2R1), glomerular PLA2R1 expression, and spontaneous remission were analysed. RESULTS: We found that variations in PLA2R1 (SNPs rs35771982, rs4664308, rs3749117) were strongly associated with IMN susceptibility, while SNP (rs2187668) within HLA-DQA1 did not increase the risk of IMN. All SNPs in PLA2R1 and HLA-DQA1 were not statistically associated with anti-PLA2R1 titre, glomerular PLA2R1 expression and spontaneous remission after Bonferroni correction (P>0.0167). Clinical and pathological parameters such as lower levels of serum albumin, higher levels of anti-PLA2R1 and glomerular PLA2R1 expression were independent risk factors for non-spontaneous remission. CONCLUSION: This study confirms that variations in PLA2R1 (SNPs rs35771982, rs4664308, rs3749117) are risk factors for IMN. We found excellent association of serum albumin level, anti-PLA2R1 titre and glomerular PLA2R1 positivity with non-spontaneous remission in IMN.

The Utility of Rise in Red Cell Distribution Width in Determining the Risk of Renal Relapse in Lupus Nephritis.

BACKGROUND: We hypothesized that the levels of red cell distribution width (RDW) would correlate with lupus nephritis (LN) disease activity, therapeutic response after induction therapy, and its rise would be associated with future renal relapse in patients who had achieved clinical remission. METHODS: The associations of RDW and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), renal response, and renal relapse after induction therapy were examined in 172 biopsy-proven LN patients at the Division of Nephrology, Huashan Hospital Fudan University between 2007 and 2017. RESULTS: The median RDW of LN patients was significantly higher than that of healthy individuals (p < 0.001). Baseline RDW demonstrated positive correlation with baseline SLEDAI (r = 0.239, p = 0.004). Overall RDW after induction treatment was significantly decreased (p = 0.005), especially in the complete remission (CR) group (p = 0.02), and the partial remission (PR) group had a decreasing trend (p = 0.09), while the change of RDW in the no response (NR) group was not statistically significant (p = 0.70). Among the 153 patients who achieved remission after induction therapies, 37 (24.2%) patients developed 42 episodes of subsequent renal flare during a median follow-up of 36.0 (IQR, 20 - 66) months. The median time from remission to renal flare was 18.0 (IQR, 7.0 - 45.0) months. The overall renal flare rate was 0.065 relapse per patient-year. During follow up, 54 RDW rises (defined as more than 0.5% increase in RDW) were identified. There were 33 episodes (61.1%) of renal flares in patients with RDW rises, while there were only 9 renal flares (8.65%) in 104 patients without RDW rise (p < 0.001). Survival analysis showed that RDW rise was associated with a significantly higher risk of future renal relapse (adjusted HR, 14.03; 95% CI, 5.29 to 37.20; p < 0.001). CONCLUSIONS: In addition to correlating with disease activity and therapeutic response to induction therapy in patients with LN, RDW rise is a significant predictor of future renal relapse in patients who achieve remission.

Calcineurin B1 subunit in human peripheral blood mononuclear cells and its role in idiopathic membranous nephropathy.

The immune responses involved in the pathogenesis of idiopathic membranous nephropathy (IMN) have not been fully understood. Calcineurin, a key signaling enzyme in T-cell activation, may be implicated in IMN. The present study aimed to investigate the role of calcineurin B1 subunit (CnB1) in IMN and the potential mechanism.A total of 59 biopsy-proven IMN patients and 28 healthy controls were recruited. The CnB1 expression in human peripheral blood mononuclear cells (PBMCs) was assessed by Western blotting. Knockdown and overexpression of CnB1 in Jurkat T cell line were achieved by small interference RNA (siRNA) transfection and lentiviral transduction, respectively.It was found that PBMCs CnB1 expression was significantly increased in IMN patients (P = .002), but unrelated to the severity and prognosis of IMN. Knockdown of CnB1 in Jurkat cells inhibited the nuclear factor of activated T cells (NFAT)-regulated gene expression required for T-cell activation.Our study suggested the potential role of CnB1 in the occurrence of IMN. The mechanism maybe involved the effect of CnB1 on the T-cell activation mediated by calcineurin-NFAT signaling.

Renal Outcomes of Pregnant Patients with Immunoglobulin A Nephropathy: A Systematic Review and Meta-Analysis.

BACKGROUND: Is the prognosis of immunoglobulin A nephropathy (IgAN) influenced by pregnancy and delivery? The answer to this question still remains to be a controversial topic. Here, we undertook a systematic review and meta-analysis to obtain the overall estimate of potential effect of IgAN and pregnancy on each other. METHODS: We systematically searched MEDLINE, EMBASE, Chinese Biological Medicine and Cochrane for cohort and case-control studies; a total of 1,378 articles were reviewed and 9 studies were included in the end. OR and mean difference (MD) were calculated with a random-effects model, kidney events and pregnancy outcomes were analyzed respectively. RESULTS: The key finding of the meta-analysis of 145 renal events in 1,198 participants was that there was no difference in renal outcomes (defined as doubling of serum creatinine (SCr), 50% decline in glomerular filtration rate [GFR] and end-stage kidney disease) of pregnant women compared with non-pregnant women who had IgAN (OR 0.90; 95% CI 0.59-1.37; p = 0.63). Subgroup analysis indicated that there was no significant difference between the 2 groups according to sample size, follow-up year, age, level of SCr and proteinuria at baseline. There was no difference in the change of the eGFR/creatinine clearance rate (mL/min/1.73 m2 per year) in IgAN patients with pregnancy compared with non-pregnancy (MD -0.11 mL/min; 95% CI -0.50-0.27; p = 0.57) as well. Women with IgAN had a higher likelihood of pregnancy outcomes compared with the Chinese general population, while they had a lower risk of preterm delivery, preeclampsia and low birth weight compared with those who had lupus nephritis or diabetic nephropathy. CONCLUSIONS: Pregnancy did not accelerate kidney disease deterioration in women with IgAN in stages of chronic kidney disease 1-3. Moreover, patients with IgAN had a relatively low risk of adverse pregnancy events compared with those with lupus nephritis or diabetic nephropathy.

The calcineurin regulatory subunit polymorphism and the treatment efficacy of tacrolimus for idiopathic membranous nephropathy.

Tacrolimus is considered to be one of the main therapeutic options for idiopathic membranous nephropathy (IMN). This study aimed to investigate the association of variants in genes encoding the binding protein and the drug target (calcineurin) of tacrolimus with the efficacy in IMN patients and the potential mechanism. Sixty-seven IMN patients treated with tacrolimus were enrolled retrospectively. Sanger sequencing was performed to search for variants in all exons of the genes in 8 IMN patients and genotype for the detected variants in the other 59 patients. The molecular mechanism underlying the relationship between the variants and the efficacy was explored in human peripheral blood mononuclear cells (PBMCs) and other cell lines. Single nucleotide polymorphism rs875 (T > C) in the 3'untranslated region (3'UTR) of PPP3R1 encoding calcineurin regulatory subunit was found to be associated with the treatment efficacy of tacrolimus for IMN. Patients carrying TT genotype had a significantly higher remission rate than those carrying TC/CC genotype (83% vs. 47%, P = 0.008). Western blot showed that the TT genotype carriers exhibited reduced PPP3R1 protein levels in PBMCs (P = 0.02). Compared with C allele, T allele displayed increased binding affinity for miR-582-5p in the luciferase reporter assay (P < 0.001). Moreover, knockdown of PPP3R1 in Jurkat T cell line enhanced the immunosuppressive effect of tacrolimus. Our study revealed the association of PPP3R1 3'UTR polymorphism rs875 with the efficacy of tacrolimus in IMN patients. The functional polymorphism might alter PPP3R1 expression via modulating the interaction of miR-582-5p with PPP3R1, which further affected the immunosuppressive effect of tacrolimus.

The role of fluorine-18 fluorodeoxyglucose PET in prognosis evaluation for stem cell transplantation of lymphoma: a systematic review and meta-analysis.

The role of fluorine-18 fluorodeoxyglucose PET (F-FDG PET) in prognostic evaluation of pre-stem cell transplantation (SCT) and post-SCT is still uncertain. A systematic review and meta-analysis were carried out to detect the prognostic power of F-FDG PET. 'PubMed', EMBASE, and Springer were searched for relevant articles. Subgroup analysis was carried out to evaluate the F-FDG PET in predicting the prognosis between Hodgkin lymphoma (HL) and non-Hodgkin lymphoma. Finally, 17 studies that included 1192 patients were eligible, 16 studies for progression-free survival (PFS) and 12 studies for overall survival (OS). For the pre-SCT PET or PET/computed tomography scan, the combined hazard ratios (HRs) of PET for PFS and OS were 2.32 and 2.64, respectively. Subgroup analysis showed that the HRs of PFS for HL and non-Hodgkin lymphoma were 3.28 and 2.00, respectively. For the post-SCT PET scan, the combined HR for PFS was 4.61. The sensitivity analysis showed that exlcusion of any single study had no significant effect on HR. We found that F-FDG PET was especially effective in predicting pre-STC and post-STC prognosis. The patients with a negative PET scan had a better prognosis compared with those with a positive scan in PFS and OS. In the subgroup analysis, F-FDG PET had a higher value in predicting prognosis before SCT for HL patients.

The predictive value of interim and final [18F] fluorodeoxyglucose positron emission tomography after rituximab-chemotherapy in the treatment of non-Hodgkin's lymphoma: a meta-analysis.

BACKGROUND AND PURPOSE: The aim of this study is to determine the prognostic value of interim and final FDG-PET in major histotypes of B-cell NHL patients treated with rituximab containing-chemotherapy. METHODS: We searched for articles published in English, limited to lymphoma, rituximab, and FDG-PET, and dedicated to deal with the impact on progression and survival. The log hazard ratios (HR) and their variances were estimated. RESULTS: A PubMed and Scopus review of published trials identified 13 studies of Progression-free survival (PFS) and overall survival (OS) which were set as the main outcome measures. The combined HRs of I-PET for PFS and OS in DLBCL were 4.4 (P = 0.11) and 3.99 (P = 0.46), respectively. The combined HRs of F-PET for PFS and OS in DLBCL were 5.91 (P = 0.39) and 6.75 (P = 0.92), respectively. Regarding to non-DLBCL with F-PET, the combined HRs of F-PET for PFS and OS were 4.05 (P = 0.79) and 5.1 (P = 0.51), respectively. No publication bias existed. CONCLUSION: In DLBCL, both I-PET and F-PET can be performed for survival and progression analysis. But in other B-cell subtypes such as follicular lymphoma (FL) and mantle cell lymphoma (MCL), it would be necessary to perform F-PET for predictive purposes.