Abstract

Background: Many studies demonstrated that roxadustat (FG-4592) could increase hemoglobin (Hb) levels effectively in anemia patients with chronic kidney disease (CKD). However, its safety remains controversial. This study aims to explore the risk of infection for CKD patients treated with roxadustat, especially focused on sepsis. Methods: We thoroughly searched for the randomized controlled trials (RCTs) comparing treatment with roxadustat versus erythropoiesis stimulating agents (ESAs) or placebo in PubMed, Embase, Cochrane Library, ClinicalTrials.gov, European Union Clinical Trials Register. Both on and not on dialysis anemia patients with CKD were included. Primary outcomes contained the incidence rates of sepsis. Secondary outcomes included infection-related consequences (septic shock and other infection events), general safety outcomes [all-cause mortality, treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)] and iron parameters. Moreover, a trial sequential analysis (TSA) was conducted to assess if the results were supposed to be a robust conclusion. Results: Eighteen RCTs (n = 11,305) were included. Overall, the incidence of sepsis (RR: 2.42, 95% CI [1.50, 3.89], p = 0.0003) and cellulitis (RR: 2.07, 95% CI [1.24, 3.44], p = 0.005) were increased in the roxadustat group compared with placebo group. In non-dialysis-dependent (NDD) CKD patients, the incidence of cellulitis (RR 2.01, 95% CI [1.23, 3.28], p = 0.005) was significantly higher in roxadustat group than that in the ESAs or placebo group. Both groups showed similar results in the incidence of septic shock (RR 1.29, 95% CI [0.86, 1.94], p = 0.22). A significant increased risk of all-cause mortality [risk ratios (RR): 1.15, 95% confidence interval (CI) [1.05, 1.26], p = 0.002] was found in roxadustat treatment, and TSA confirmed the result. Compared with ESAs or placebo, both the incident rates of TEAEs (RR:1.03, 95% CI [1.01, 1.04], p = 0.008) and TESAEs (RR: 1.06, 95% CI [1.02, 1.11], p = 0.002) were significantly increased in roxadustat group. As for iron parameters, changes from baseline (Δ) of hepcidin (MD: -26.46, 95% CI [-39.83, -13.09], p = 0.0001), Δ ferritin and Δ TSAT were remarkably lower in the roxadustat group, while Δ Hb, Δ iron and Δ TIBC increased significantly versus those in ESAs or placebo group. Conclusion: We found evidence that incidence rates of sepsis and cellulitis are higher in roxadustat group compared with placebo. This may be the result of improved iron homeostasis. The risk of all-cause mortality, TEAEs and TESAEs in CKD patients also increased in patients treated with roxadustat. We need more clinical and mechanistic studies to confirm whether roxadustat really causes infection.

Abstract

BACKGROUND Edema is one of the cardinal clinical features of nephrotic syndrome (NS). It may vary from mild periorbital edema to severe generalized edema (anasarca). In patients where edema does not improve with prednisone therapy, the most common supportive medications are diuretics and albumin. However, due to the complex pathophysiology of edema formation in NS patients resulting in intravascular normovolemia or hypovolemia, optimal therapy for edema is still debated. We conducted a systematic review with the objective of evaluating the change in urine volume and urine sodium excretion after treatment with furosemide only versus furosemide with albumin in edematous patients with NS. OBJECTIVES (1) To evaluate efficacy of furosemide alone versus furosemide with albumin in the treatment of nephrotic edema in adults and children. (2) To compare the harms and benefits of different doses of furosemide for treating nephrotic edema. SEARCH METHODS The search included all randomized or quasi-randomized controlled trials in English and French using MEDLINE, Embase, and CENTRAL Trials Registry of the Cochrane Collaboration using the Ovid interface. ClinicalTrials.gov and the International Clinical Trials Registry Platform were also searched. SELECTION CRITERIA We included all RCTs and randomized cross-over studies in which furosemide and furosemide plus albumin are used in the treatment of children or adults with nephrotic edema. We excluded patients with hypoalbuminemia of non-renal origin and severe chronic kidney disease (CKD) with a glomerular filtration rate below 30 ml/min/1.74 m(2) and patients with congenital NS. DATA COLLECTION AND ANALYSIS All abstracts were independently assessed by at least two authors to determine which studies met the inclusion criteria. Information on study design, methodology, and outcome data (urine volume, urine sodium excretion, adverse effects) from each identified study was entered into a separate data sheet. The differences in outcomes between the types of therapy were expressed as standardized mean difference (SMD) with 95% confidence intervals (CI). RESULTS The search yielded 525 records, and after screening, five studies were included in the systematic review and four of those studies in the meta-analysis. One study had high risk of bias and the remaining three studies were deemed to have some concerns. Urine excretion was greater after treatment with furosemide and albumin versus furosemide (SMD 0.85, 95% CI = 0.33 to 1.38). Results for sodium excretion were inconclusive (SMD 0.37, 95%CI =  - 0.28 to 1.02). AUTHORS' CONCLUSIONS The current evidence is not sufficient to make definitive conclusions about the role of albumin in treating nephrotic edema. High-quality randomized studies with adequate samples sizes are needed. Including an assessment of intravascular volume status may be helpful. TRIAL REGISTRATION Prospero: CRD4201808979. https://www.crd.york.ac.uk/PROSPERO A higher resolution version of the Graphical abstract is available as Supplementary information.

Abstract

BACKGROUND Erythropoiesis-stimulating agents (ESAs) revolutionized the management of anaemia in chronic kidney disease (CKD) when introduced in the late 1980s. A range of ESA types, preparations and administration modalities now exist, with newer agents requiring less frequent administration. Although systematic reviews and meta-analyses have been published in adults, no systematic review has been conducted investigating ESAs in children. METHODS The Preferred Reporting Items for Systematic Reviews and Meta-analyses statement for the conduct of systematic reviews was used. All available literature on outcomes relating to ESAs in children with CKD was sought. A search of the MEDLINE, CINAHL and Embase databases was conducted by two independent reviewers. Inclusion criteria were published trials in English, children with chronic and end-stage kidney disease and use of any ESA studied against any outcome measure. An assessment of risk of bias was carried out in all included randomized trials using the criteria from the Cochrane Handbook for Systematic Reviews of Interventions. Two tables were used for data extraction for randomized and observational studies. Study type, participants, inclusion criteria, case characteristics, follow-up duration, ESA type and dosage, interventions and outcomes were extracted by one author. RESULTS Of 965 identified articles, 58 were included covering 54 cohorts. Six were randomized trials and 48 were observational studies. A total of 38 studies assessed the efficacy of recombinant human erythropoietin (rHuEPO), 11 of darbepoetin alpha (DA) and 3 of continuous erythropoietin receptor activator (CERA), with 6 studies appraising secondary outcome measures exclusively. Recruitment to studies was a consistent challenge. The most common adverse effect was hypertension, although confounding effects often limited direct correlation. Two large cohort studies demonstrated a greater hazard of death independently associated with high ESA dose. Secondary outcome measures included quality of life measures, growth and nutrition, exercise capacity, injection site pain, cardiovascular function, intelligent quotient, evoked potentials and platelet function. CONCLUSIONS All ESA preparations and modes of administration were efficacious, with evidence of harm at higher doses. Evidence supports individualizing treatments, with strong consideration given to alternate treatments in patients who appear resistant to ESA therapy. Further research should focus on randomized trials comparing the efficacy of different preparations, treatment options in apparently ESA-resistant cohorts and clarification of meaningful secondary outcomes to consolidate patient-relevant indices.

Abstract

Introduction: Daprodustat, a novel hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI), its efficacy and safety remain unclear. Thus, we conducted this meta-analysis aiming at investigating its efficacy and safety on the treatment of patients with chronic kidney disease (CKD)-related anemia. Methods: We systematically searched for relevant studies in PubMed, Embase, Cochrane Library and Clinical Trial Registries databases from inception until December 2021. We selected randomized controlled trials comparing daprodustat with recombinant human erythropoietin (rhEPO) in anemia patients with CKD with or without dialysis. Results: Seven studies including 7933 patients met the inclusion criteria. For both nondialysis-dependent (NDD-) CKD and dialysis-dependent (DD-) CKD patients, the pooled results showed that there was no significant difference in the changes in hemoglobin levels between the daprodustat and rhEPO groups (mean difference (MD) = -0.01, 95% confidence interval (CI) = -0.38, 0.35, p = 0.95; MD = 0.15, 95% CI = -0.29, 0.60, p = 0.50; respectively). In addition, a significant increase in transferrin saturation (TSAT), total iron binding capacity (TIBC) and total iron was observed in daprodustat groups compared with rhEPO groups in DD-CKD patients (p < 0.05). As for safety, the overall frequency of adverse events was similar between the daprodustat and rhEPO groups in DD-CKD patients (relative risk (RR) = 0.99, 95%CI = 0.92, 1.06, p = 0.76), and the trial sequential analysis (TSA) confirmed this result. But for NDD-CKD patients, the incidence of adverse events in the daprodustat groups was significantly higher than that of rhEPO groups (RR = 1.04, 95%CI = 1.01,1.07, p = 0.02), while the TSA corrected this result. No trend of increasing incidence of serious adverse events was found in all daprodustat treated patients, but the TSA could not confirm this result. Conclusion: Although daprodustat was noninferior to rhEPO in correcting anemia in both NDD-CKD and DD-CKD patients, it seemed to have a better effect on optimizing iron metabolism in DD-CKD patients. Daprodustat may be a promising alternative for the treatment of anemia in patients with CKD. However, due to the lack of included studies, future researches are needed to further evaluate the therapeutic effect of daprodustat. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021229636.

Abstract

INTRODUCTION AND OBJECTIVE Intravenous immunoglobulin (IVIg) is an anti-inflammatory drug with an unclear role in the treatment of patients with lupus nephritis (LN). This systematic review evaluates the evidence for IVIg in the care of patients with LN. METHODOLOGY A systematic search was done in the PubMed, EMBASE, BVS and OVID databases - All EBM Reviews following the PRISMA methodology (registration in PROSPERO CRD42021236662). The variables were extracted: indications for use, dosage, partial or complete response, adverse reactions, initiation of renal replacement therapy, reduction of proteinuria, and mortality. The quality assessment was done with the "The Joanna Briggs Institute (JBI) Critical Appraisal tools for use in Systematic Reviews Checklist". In addition, synthesis reports were prepared through the Synthesis Without Meta-analysis - SWiM guide. RESULTS A total of 2328 articles were obtained (28 were considered for inclusion). When the studies were evaluated, IVIg therapy was found to be between 60% to 70% effective (except for patients with class V LN) with overall responses (complete + partial) even for patients who are refractory to first line treatment. Normalization (<0.5 g) of nephrotic proteinuria occurred in 24% of cases with infrequent adverse events and a mortality plus dialysis composite of 11.5% and 24.1% (most representative study). CONCLUSION In patients with LN refractory to conventional treatment or co-infection situations, the reported data seem to demonstrate effectiveness of IVIg therapy. There are few adverse reactions and caution is exercised when using it on patients with class V NL. However, given the lack of controlled studies with long-term follow-up, these data should be interpreted cautiously thus encouraging the development of high-quality RCTs.

Abstract

OBJECTIVE As a novel oral agent in treating anemia of chronic kidney disease (CKD), several clinical trials of vadadustat have been conducted to compare with darbepoetin alfa. This study systematically reviews and investigates the efficacy and safety of vadadustat in the anemia treatment with different duration in both nondialysis-dependent CKD (NDD-CKD) and dialysis-dependent CKD (DD-CKD). METHODS Several main databases were searched for randomized controlled trials (RCTs) reporting vadadustat vs darbepoetin alfa for anemia patients with CKD. The outcome indicators were focused on hemoglobin (Hb), the percentage of patients within the target Hb, the need for RBC (Red Blood Cell) transfusions, and serious adverse events (SAEs). RESULTS Four eligible studies with 8,026 participants were included. The changes of Hb levels from the baseline in the darbepoetin alfa group were significantly higher than that in the vadadustat group with DD-CKD (mean difference (MD) - 0.19, [95% confidence interval (CI), - 0.21 to - 0.17], p < 0.0001). In NDD-CKD patients, the changes of Hb levels in the two groups are not significantly different (MD = - 0.06, [95% CI, - 0.18 to 0.05], p = 0.006), especially, during the treatment duration of 20-36 weeks (MD = 0.02, [95% CI, - 0.04 to 0.08], p = 0.51). The percentage of patients within the target Hb was significantly lower in the vadadustat group than that in the darbepoetin alfa group in DD-CKD patients (MD = 0.9, [95% CI, 0.86 to 0.94], p < 0.00001), while in NDD-CKD patients, there was no significant difference (MD = 1.05, [95% CI, 0.99 to 1.12], p < 0.00001). In terms of safety, the two agents had no significant difference in the incidence of RBC transfusions and SAEs (RR = 1.26 [95% CI, 0.99 to 1.61], p = 0.52; RR = 0.97, [95% CI, 0.94 to 1.01], p = 0.19; respectively). CONCLUSION Compared to darbepoetin alfa, vadadustat had the same effect in raising the hemoglobin level in NDD-CKD patients in the short term. Vadadustat may become an effective and safe alternative for the treatment of patients with anemia and CKD, especially in NDD-CKD patients. As the application of vadadustat is still under exploration, future research should compensate for the limitations of our study to estimate the vadadustat's value.

Abstract

BACKGROUND Roxadustat (ROX) is a new medication for anemia as a complication of chronic kidney disease (CKD). Our meta-analysis aims to evaluate the efficacy and safety of ROX, especially on the cardiovascular risks, for anemia in NDD-CKD patients. METHODS Electronic databases were searched systematically from inception to July 2021 to look for randomized control trials (RCTs) that evaluated ROX NDD-CKD patients. Hemoglobin level and iron utilization parameters, including ferritin, serum iron, transferrin saturation (TSAT), total iron-binding capacity (TIBC), transferrin, and hepcidin were analyzed for efficacy. Pooled risk ratios (RRs) and standardized mean differences (SMDs) were calculated and presented with their 95% confidential intervals (CIs). RESULTS Nine RCTs included a total of 3,175 patients in the ROX group and 2,446 patients in the control group. When compared the control group, ROX increased Hb level significantly (SMD: 1.65; 95% CI: 1.08, 2.22; P< 0.00001) and improved iron utilization parameters by decreasing ferritin (SMD: -0.32; 95% CI: -0.51, -0.14; P = 0.0006), TSAT (SMD: -0.19; 95% CI: -0.32, -0.07; P = 0.003), and hepcidin (SMD: -0.74; 95% CI: -1.09, -0.39; P< 0.0001) and increasing TIBC (SMD: 0.99; 95% CI: 0.76, 1.22; P< 0.00001) and transferrin (SMD: 1.20; 95% CI: 0.70, 1.71; P< 0.00001). As for safety, ROX was associated with higher serious adverse effects (RR: 1.07; 95% CI: 1.01, 1.13; P = 0.01), deep venous thrombosis (DVT) (RR: 3.80; 95% CI: 1.5, 9.64; P = 0.08), and hypertension (HTN) (RR: 1.37; 95% CI: 1.13, 1.65; P = 0.001). CONCLUSION We concluded that ROX increased Hb level and improved iron utilization parameters in NDD-CKD patients, but ROX was associated with higher serious adverse effects, especially DVT and HTN. Our results support the use of ROX for NDD-CKD patients with anemia. However, higher-quality RCTs are still needed to ensure its safety and risk of thrombosis.

Abstract

Nephrotic syndrome (NS) affects 115-169 children per 100,000, with rates varying by ethnicity and location. Immune dysregulation, systemic circulating substances, or hereditary structural abnormalities of the podocyte are considered to have a role in the etiology of idiopathic NS. Following daily therapy with corticosteroids, more than 85% of children and adolescents (often aged 1 to 12 years) with idiopathic nephrotic syndrome have full proteinuria remission. Patients with steroid-resistant nephrotic syndrome (SRNS) do not demonstrate remission after four weeks of daily prednisolone therapy. The incidence of steroid-resistant nephrotic syndrome in children varies between 35 and 92 percent. A third of SRNS patients have mutations in one of the important podocyte genes. An unidentified circulating factor is most likely to blame for the remaining instances of SRNS. The aim of this article is to explore and review the genetic factors and management of steroid-resistant nephrotic syndrome. An all language literature search was conducted on MEDLINE, COCHRANE, EMBASE, and Google Scholar till September 2021. The following search strings and Medical Subject Headings (MeSH) terms were used: "Steroid resistance", "nephrotic syndrome", "nephrosis" and "hypoalbuminemia". We comprehensively reviewed the literature on the epidemiology, genetics, current treatment protocols, and management of steroid-resistant nephrotic syndrome. We found that for individuals with non-genetic SRNS, calcineurin inhibitors (cyclosporine and tacrolimus) constitute the current mainstay of treatment, with around 70% of patients achieving full or partial remission and an acceptable long-term prognosis. Patients with SRNS who do not react to calcineurin inhibitors or other immunosuppressive medications may have deterioration in kidney function and may develop end-stage renal failure. Nonspecific renal protective medicines, such as angiotensin-converting enzyme inhibitors, angiotensin 2 receptor blockers, and anti-lipid medications, slow the course of the illness. Recurrent focal segmental glomerulosclerosis in the allograft affects around a third of individuals who get a kidney transplant, and it frequently responds to a combination of plasma exchange, rituximab, and increased immunosuppression. Despite the fact that these results show a considerable improvement in outcome, further multicenter controlled studies are required to determine the optimum drugs and regimens to be used.

Abstract

Fibroblast growth factor 23 (FGF23) gene is found to be responsible for autosomal dominant hypophosphatemic rickets, and is highly expressed in chronic kidney disease (CKD) and end-stage renal disease patients with iron deficiency anemia (IDA). We evaluated the efficacy of different iron treatments on FGF23 levels in dialysis-dependent and non-dialysis-dependent CKD patients with IDA. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing different types of iron treatment versus placebo in CKD patients up to May 2020. We investigated the efficacy of iron treatment on the levels of FGF23 and C-terminal FGF23 (cFGF23) in CKD patients. We estimated weighted mean differences (WMDs) and 95% confidence intervals (CIs) using the random-effects model. Nine studies with 11 arms were included in the meta-analysis. Overall, iron treatment showed a significant reduction in FGF23 levels compared to control group (WMD: - 60.56 pg/ml, 95% CI: - 92.17, - 28.95). Compared to placebo, subgroup analysis showed that oral iron therapy (WMD: - 6.98 pg/ml, 95% CI: - 10.66, - 3.31) was more effective than intravenous (IV) iron therapy (WMD: 4.90 pg/ml, 95% CI: - 12.03, 21.83) on FGF23 levels. There was no significant change in cFGF23 levels between iron treatment and control group (WMD: - 64.72 Ru/ml, 95% CI: - 147.69, 18.25). Subgroup analysis showed that oral iron therapy resulted in a significant reduction in cFGF23 levels compared to control group (WMD: - 150.48 RU/ml, 95% CI: - 151.31, - 149.65). In conclusion, iron treatment was associated with a significant decrease in FGF23 levels in CKD patients.

Abstract

BACKGROUND Anemia is a common complication for patients with kidney disease. Roxadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI), which is a newly approved oral drug for anemia. We performed this study to build evidence regarding efficacy and safety of roxadustat in kidney disease patients with or without dialysis. METHODS We searched the databases of PubMed, Embase, Cochrane library and clinicaltrials.gov from the inception to July 20, 2020. The randomized controlled trials (RCTs) which compared roxadustat with placebo or other therapies in the treatment of anemia in kidney disease patients were included. Data were extracted from eligible studies and pooled in a meta-analysis model using RevMan5.3 and stata13.0 software. RESULTS Eight RCTs with 1010 patients were included in our analysis. We found that roxadustat significantly increased hemoglobin (Hb) level (1.10 g/dL, 95% CI [0.52 g/dL, 1.67 g/dL], p = 0.0002), total iron-binding capacity (TIBC) (58.71 µg/dL, 95% CI [44.10 µg/dL, 73.32 µg/dL], p < 0.00001), iron level (9.28 µg/dL, 95% CI [0.11 µg/dL, 18.45 µg/dL], p = 0.05) compared with control group in kidney disease patients. In addition, our result showed that a significant reduction in hepcidin level (- 31.96 ng/mL, 95% CI [- 35.05 ng/mL, - 28.87 ng/mL], p < 0.00001), ferritin (- 44.82 ng/mL, 95% CI [- 64.42 ng/mL, - 25.23 ng/mL], p < 0.00001) was associated with roxadustat. No difference was found between roxadustat and control group in terms of oral iron supplementation, adverse events (AEs), serious adverse events (SAEs), infection, myocardial infraction, stroke, heart failure and death. CONCLUSIONS Roxadustat has higher mean Hb level than placebo or EPO. Due to the short follow-up period and the lack of critical data, more RCTs are needed to prove long-term safety and effectiveness of roxadustat in the future.