Investigating Brain Functional Connectivity and Its Correlation With Cognitive Dysfunction in Chronic Kidney Disease Patients via Resting‐State fMRI

Background and Aims Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is approved in multiple countries for the treatment of anemia of chronic kidney disease (CKD). Previous pooled analyses have reported that roxadustat was non-inferior to erythropoiesis-stimulated agents (ESAs) for time to first major adverse cardiovascular event (MACE) and MACE plus congestive heart failure (CHF) or unstable angina requiring hospitalization in patients with dialysis-dependent (DD) or non–dialysis-dependent (NDD) CKD; however, these analyses were not stratified by history of CHF. The current post hoc analysis was conducted to evaluate time to first hospitalization for CHF in patients with DD or NDD CKD with or without a history of CHF treated with roxadustat compared with ESA. Method Patients with anemia of CKD from four phase 3, multicenter, randomized, open-label, active-comparator studies (HIMALAYAS, ROCKIES, SIERRAS, and PYRENEES) were pooled for the DD CKD group, and patients from a phase 3, multicenter, randomized, open-label, active-comparator study (DOLOMITES) were analyzed as the NDD CKD group. Data were analyzed for the time to first occurrence of hospitalization for CHF during and up to 7 days after the treatment period (ie, on-treatment plus 7 days) using a separate model for each of the four groups (DD CKD with a history of CHF, DD CKD without a history of CHF, NDD CKD with a history of CHF, and NDD CKD without a history of CHF). Hazard ratios (HRs) were estimated with a Cox proportional hazards model adjusted for baseline age as a continuous covariate. The non-inferiority margin was set at 1.8, as recommended by industry guidance provided by health authority bodies regarding the assessment of cardiovascular risk in clinical studies. Results Of the 4714 patients with DD CKD (roxadustat: n = 2354; ESA: n = 2360), 1122 had a history of CHF (roxadustat: n = 562; ESA: n = 560). Of the 616 patients with NDD CKD (roxadustat: n = 323; ESA: n = 293), 158 had a history of CHF (roxadustat: n = 81; ESA: n = 77). In the DD CKD group, treatment with roxadustat demonstrated noninferiority to ESA treatment in patients with no history of CHF (HR [95% CI]: 0.85 [0.64, 1.14]) and in patients with a history of CHF (0.97 [0.67, 1.39]; Table 1), both with the upper limit of the confidence limit less than the non-inferiority margin of 1.8. In the NDD CKD group, treatment with roxadustat demonstrated noninferiority to ESA treatment in patients with a history of CHF (0.62 [0.25, 1.51]). The noninferiority margin was not achieved (upper limit of the confidence interval ≥1.8) in patients with NDD CKD with no history of CHF (1.31 [0.57, 2.99]; Table 1). These results are difficult to interpret due to the low number of events included in the analysis; this increased uncertainty is evident in the wider confidence interval. Conclusion In patients with DD CKD, regardless of history of CHF, and in patients with NDD CKD with a history of CHF, the results from this post hoc analysis suggest that treatment with roxadustat is non-inferior to ESA for the risk of hospitalization for CHF. In patients with NDD CKD without a history of heart failure, the results should be interpreted cautiously due to the low number of events included in this analysis.

Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, increases hemoglobin by stimulating erythropoietin synthesis and improving iron availability through facilitation of iron uptake and/or release from stores. In this exploratory analysis, we assessed the effect of roxadustat treatment on laboratory parameters related to iron metabolism in patients with anemia of chronic kidney disease (CKD). Data were pooled from pivotal, randomized, phase 3 roxadustat trials: three placebo-controlled, double-blind trials in nondialysis-dependent (NDD) CKD and three open-label, active-comparator (epoetin alfa) trials in dialysis-dependent (DD) CKD. In this exploratory analysis, mean changes from baseline in hemoglobin, iron parameters, and hepcidin, and intravenous (iv) iron use were evaluated. Pooled results in NDD CKD and DD CKD patients are reported. Overall, 4277 patients with NDD CKD and 3890 patients with DD CKD were evaluated. Hemoglobin increases with roxadustat treatment were accompanied by increases in serum iron and total iron-binding capacity (TIBC) and decreases in serum ferritin and hepcidin from baseline through week 52. With epoetin alfa, the hemoglobin increase was accompanied by decreases in serum ferritin and hepcidin, but serum iron decreased, and there was no change in TIBC. With placebo, there were no changes in hemoglobin, iron parameters, or hepcidin. During treatment, iv iron use was reduced with roxadustat versus placebo and epoetin alfa. In patients with NDD CKD and DD CKD, roxadustat treatment is associated with increases in serum iron and TIBC, accompanied by reduced hepcidin and indicative of improved iron kinetics. Patients treated with roxadustat achieved target hemoglobin levels with less iv iron use versus comparators. Practitioners treating patients with anemia of CKD with roxadustat should consider its unique effects when interpreting iron parameters.

In individuals with chronic kidney disease (CKD), neurological damage is commonly observed. This neurodegeneration is closely linked to microstructural damage to the brain white matter due to the high incidence of cognitive dysfunction. However, the specific pathogenesis of CKD nephropathy caused by cognitive system developmental disorders remains unclear. This study aimed to examine the correlation between cognitive impairment and diffusion parameters obtained on diffusion tensor imaging (DTI) of abnormal white matter tracts in CKD patients. Sixty-four patients with CKD were divided into the non-dialysis-dependent CKD (NDD-CKD) group (N = 26) and dialysis-dependent CKD (DD-CKD) group (N = 38) according to the estimated glomerular filtration rate, whereas 43 healthy control subjects (normal control [NC]) were included and underwent cranial magnetic resonance imaging during the same period. Differences in the abnormal white matter microstructure and correlations between them and cognitive scores were assessed using several parameters between the groups. There were more extensive peri-lesions and distant white matter microstructural changes in the DD-CKD and NDD-CKD groups than in the NC group. DTI diffusion parameters in abnormal white matter regions were associated with impaired cognitive function in CKD patients. The DD-CKD group had worse cognitive function and more severe microstructural damage in the cerebral white matter than the NDD-CKD group. CKD patients showed cognitive impairment and changes in the brain white matter microstructure; CKD can lead to extensive white matter tract damage. Additionally, diffusion parameters can be used as a complement to describe structural brain damage in CKD patients.

The Impact of Intravenous Iron on Renal Injury and Function Markers in Patients With Chronic Kidney Disease and Iron Deficiency Without Anemia

BackgroundHypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors are an oral treatment for anemia of chronic kidney disease (CKD). In this systematic review and meta-analysis, we assessed long-term safety of HIF prolyl hydroxylase inhibitors.MethodsWe searched MEDLINE, Embase, and Cochrane databases for randomized trials comparing HIF prolyl hydroxylase inhibitors with an erythropoiesis-stimulating agent (ESA) or placebo with greater than or equal to 48 weeks of follow-up. The primary outcome was major adverse cardiovascular event (MACE), defined as a composite of all-cause death, myocardial infarction, or stroke. Treatment effects were pooled using random-effects models.ResultsTwenty-five trials involving 26,478 participants were included. Of these, 13 trials enrolled 13,230 participants with dialysis-dependent CKD, and 12 trials enrolled 13,248 participants with nondialysis-dependent CKD. There was no evidence that HIF prolyl hydroxylase inhibitors and ESA had different effects on MACE in people with dialysis-dependent CKD (risk ratio, 0.99; 95% confidence interval [CI], 0.92 to 1.08) or people with nondialysis-dependent CKD (risk ratio, 1.08; 95% CI, 0.95 to 1.22). Similarly, there was no evidence that HIF prolyl hydroxylase inhibitors and placebo had different effects on MACE (risk ratio, 1.10; 95% CI, 0.96 to 1.27) in people with nondialysis-dependent CKD. The lack of difference between HIF prolyl hydroxylase inhibitors and ESA or placebo was observed for individual components of MACE and cardiovascular death. Safety of HIF prolyl hydroxylase inhibitors for other outcomes was comparable with ESA in dialysis-dependent CKD. In nondialysis-dependent CKD, dialysis access thrombosis, venous thromboembolism, infections, and hyperkalemia occurred more frequently with HIF prolyl hydroxylase inhibitors in placebo-controlled trials but not in ESA-controlled trials.ConclusionsThere was no evidence of a difference in the long-term cardiovascular safety profile of HIF prolyl hydroxylase inhibitors and ESA in adults with dialysis-dependent CKD and adults with nondialysis-dependent CKD. (PROSPERO registration number, CRD42021278011.)

Cardiovascular disease accounts for the majority of deaths in chronic kidney disease (CKD). Dyslipidemia is a well established cardiovascular risk factor. We summarize key aspects of available evidence relating to beneficial effects of statins in nondialysis-dependent CKD, dialysis-dependent CKD and renal transplant recipients. Previous trials and their meta-analyses suggested that statins reduce lipid levels, the risk of cardiovascular disease and all-cause mortality in nondialysis-dependent CKD. The Study of Heart and Renal Protection (SHARP) study that enrolled both dialysis-dependent and nondialysis-dependent CKD patients showed a 17% decrease in major atherosclerotic events with statins or ezetimibe. Similar cardiovascular benefits are observed in renal transplant recipients. However, such positive effects were not found in two recent clinical trials that enrolled hemodialysis patients alone. This lack of benefit might be attributed to differences in the cause of cardiovascular death seen in dialysis patients and smaller sample size. The overall benefits-harms tradeoff may benefit from meta-analysis and individual patient data meta-analysis in hemodialysis patients including the SHARP data. Nondialysis-dependent CKD patients and renal transplant recipients benefit from statins. Statins have also been found to be beneficial in one of the three large trials in hemodialysis patients, a matter which may be further explored.

Objective Cataract and chronic kidney disease (CKD) occur with increasing frequency with age and share common risk factors including smoking, diabetes, and hypertension. We evaluated the risk of incident cataract surgery in patients with non-dialysis-dependent CKD and dialysis-dependent CKD compared to non-CKD patients, while taking into account the competing risk of death. Methods The participants included 1,839 patients from Sado General Hospital enrolled in the Project in Sado for Total Health (PROST) between June 2008 and December 2016 (54% men; mean age, 69 years). Among these patients, 50%, 44%, and 6% had non-CKD, non-dialysis-dependent CKD, and dialysis-dependent CKD, respectively. Results During a median follow-up of 5.6 years (interquartile range, 4.7-7.1), 193 participants underwent cataract surgery [18.7 (95% confidence interval (CI), 16.2-21.5)/1,000 person-years] and 425 participants died without undergoing cataract surgery [41.0 (95% CI, 37.4-45.2)/1,000 person-years]. The cumulative incidence of cataract surgery was the highest in the dialysis-dependent CKD group, followed by the non-dialysis-dependent CKD and non-CKD groups (log-rank p=0.002). After adjusting for potential confounding factors, the dialysis-dependent CKD group [hazard ratio (HR) 2.48; 95% CI 1.43-4.31], but not the non-dialysis-dependent CKD group (HR, 1.01; 95% CI 0.74-1.38), had a higher risk of cataract surgery than the non-CKD group. However, this association was no longer significant according to a competing risk analysis (sub-hazard ratio, 1.67; 95% CI 0.93-3.03). Conclusion Dialysis-dependent CKD patients were found to have an increased risk of cataract surgery; however, the association was attenuated and no longer significant when death was considered a competing risk.

Nomenclature for kidney function and disease: Executive summary and glossary from a Kidney Disease: Improving Global Outcomes (KDIGO) consensus conference

BackgroundThis meta-analysis was conducted to evaluate the differences in preoperative comorbidities, postoperative mortality, the rate of periprosthetic joint infection (PJI), and revision rate after total joint arthroplasty (TJA) between patients with chronic kidney disease (CKD)(CKD group) and patients with normal kidney function (non-CKD group).MethodsWe searched MEDLINE, EMBASE, and the Cochrane Library for studies assessing the effect of CKD on TJA outcome. This meta-analysis included studies that (1) compared the outcomes of TJA between the CKD and non-CKD groups; (2) compared the outcomes of TJA based on CKD stage; and (3) evaluated the risk factors for morbidity or mortality after TJA. We compared the mortality, PJI, and revision rate between CKD and non-CKD groups, and between dialysis-dependent patients (dialysis group) and non-dialysis-dependent patients (non-dialysis group).ResultsEighteen studies were included in this meta-analysis. In most studies that assessed preoperative comorbidities, the number and severity of preoperative comorbidities were reported to be higher in the CKD group than in the non-CKD group. The risk of mortality was found to be higher in the CKD and dialysis groups compared with the respective control groups. In the studies based on administrative data, the unadjusted odds ratio (OR) of PJI was significantly higher in the CKD group than in the non-CKD group; however, no significant difference between the groups was noted in the adjusted OR. After total hip arthroplasty (THA), the risk of PJI was higher in the dialysis group than in the non-dialysis group. No significant difference was noted between the groups in the rate of PJI following total knee arthroplasty. The revision rate did not significantly differ between the CKD and non-CKD groups in the studies that were based on administrative data. However, the unadjusted OR was significantly higher in the dialysis group than in the non-dialysis group.ConclusionsPreoperative comorbidities and mortality risk were higher in the CKD and dialysis groups than in their respective control groups. The risk of revision was greater in the dialysis group than in the non-dialysis group, and the risk of PJI in the dialysis group became even greater after THA. Surgeons should perform careful preoperative risk stratification and optimization for patients with CKD scheduled to undergo TJA.

The Outcomes of Chronic Kidney Disease and Heart Failure with Reduced Ejection Fraction

Medical Nutrition Therapy for Patients with Non–Dialysis-Dependent Chronic Kidney Disease: Barriers and Solutions

Renal Impairment, Cardiovascular Disease, and the Short-Term Efficacy and Safety of PCSK9 Targeted by Inclisiran

Background: Chronic kidney disease is a major public health problem worldwide. As kidney function declines, it leads to several metabolic abnormalities including dysregulation of mineral metabolism. It is also reported that hyperphosphatemia in patients with advanced kidney disease is associated with an increased risk of mortality and cardiovascular events, and is higher in dialysis-dependent chronic kidney disease (CKD) patients compared to non-dialysis CKD. However, data in the Indian context is limited. Objectives were to evaluate and compare serum phosphorus levels and associated factors in non-dialysis and dialysis CKD patients. Also, the impact of dietary phosphate restriction and the use of phosphate binders on serum phosphorus is analysed. Methods: A cross-sectional study was conducted at a tertiary care hospital in Kolkata, India, with 100 CKD patients: 50 non-dialysis CKD patients and 50 dialysis-dependent CKD patients. Relevant demographic, clinical and laboratory parameters including serum phosphorus, calcium, parathyroid hormone (PTH), alkaline phosphatase, albumin and estimated glomerular filtration rate (eGFR) were collected. Data was analyzed using appropriate statistical tests. Results: Mean serum phosphorus was significantly higher in the dialysis CKD group (6.12±0.34 mg/dl) compared to the non-dialysis CKD group (4.56±0.80 mg/dl). Serum calcium and PTH were also higher while eGFR and albumin were lower in the dialysis CKD group. Serum phosphorus levels increased with advancing CKD stages in the non-dialysis group. Phosphate binder helped phosphorus control in dialysis CKD patients. Conclusions: Our study is in confluence with other reports and dietary phosphate restriction and the use of phosphate binders help optimize phosphorus levels in CKD patients.

Cognition in People With End-Stage Kidney Disease Treated WithHemodialysis: A Systematic Review and Meta-analysis.

Brain Atrophy in Peritoneal Dialysis and CKD Stages 3-5: A Cross-sectional and Longitudinal Study