Renin-Angiotensin System Inhibition in Advanced Chronic Kidney Disease.

BACKGROUND: Renin-angiotensin system (RAS) inhibitors - including angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) - slow the progression of mild or moderate chronic kidney disease. However, the results of some studies have suggested that the discontinuation of RAS inhibitors in patients with advanced chronic kidney disease may increase the estimated glomerular filtration rate (eGFR) or slow its decline. METHODS: In this multicenter, open-label trial, we randomly assigned patients with advanced and progressive chronic kidney disease (eGFR, <30 ml per minute per 1.73 m2 of body-surface area) either to discontinue or to continue therapy with RAS inhibitors. The primary outcome was the eGFR at 3 years; eGFR values that were obtained after the initiation of renal-replacement therapy were excluded. Secondary outcomes included the development of end-stage kidney disease (ESKD); a composite of a decrease of more than 50% in the eGFR or the initiation of renal-replacement therapy, including ESKD; hospitalization; blood pressure; exercise capacity; and quality of life. Prespecified subgroups were defined according to age, eGFR, type of diabetes, mean arterial pressure, and proteinuria. RESULTS: At 3 years, among the 411 patients who were enrolled, the least-squares mean (±SE) eGFR was 12.6±0.7 ml per minute per 1.73 m2 in the discontinuation group and 13.3±0.6 ml per minute per 1.73 m2 in the continuation group (difference, -0.7; 95% confidence interval [CI], -2.5 to 1.0; P = 0.42), with a negative value favoring the outcome in the continuation group. No heterogeneity in outcome according to the prespecified subgroups was observed. ESKD or the initiation of renal-replacement therapy occurred in 128 patients (62%) in the discontinuation group and in 115 patients (56%) in the continuation group (hazard ratio, 1.28; 95% CI, 0.99 to 1.65). Adverse events were similar in the discontinuation group and continuation group with respect to cardiovascular events (108 vs. 88) and deaths (20 vs. 22). CONCLUSIONS: Among patients with advanced and progressive chronic kidney disease, the discontinuation of RAS inhibitors was not associated with a significant between-group difference in the long-term rate of decrease in the eGFR. (Funded by the National Institute for Health Research and the Medical Research Council; STOP ACEi EudraCT number, 2013-003798-82; ISRCTN number, 62869767.).

ß2-Adrenergic receptor agonists as a treatment for diabetic kidney disease.

We have previously shown that the long-acting ß2-adrenergic receptor (ß2-AR) agonist formoterol induced recovery from acute kidney injury in mice. To determine whether formoterol protected against diabetic nephropathy, the most common cause of end-stage kidney disease (ESKD), we used a high-fat diet (HFD), a murine type 2 diabetes model, and streptozotocin, a murine type 1 diabetes model. Following formoterol treatment, there was a marked recovery from and reversal of diabetic nephropathy in HFD mice compared with those treated with vehicle alone at the ultrastructural, histological, and functional levels. Similar results were seen after formoterol treatment in mice receiving streptozotocin. To investigate effects in humans, we performed a competing risk regression analysis with death as a competing risk to examine the association between Veterans with chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), who use ß2-AR agonists, and Veterans with CKD but no COPD, and progression to ESKD in a large national cohort of Veterans with stage 4 CKD between 2011 and 2013. Veterans were followed until 2016 or death. ESKD was defined as the initiation of dialysis and/or receipt of kidney transplant. We found that COPD was associated with a 25.6% reduction in progression from stage 4 CKD to ESKD compared with no COPD after adjusting for age, diabetes, sex, race-ethnicity, comorbidities, and medication use. Sensitivity analysis showed a 33.2% reduction in ESKD in Veterans with COPD taking long-acting formoterol and a 20.8% reduction in ESKD in Veterans taking other ß2-AR agonists compared with those with no COPD. These data indicate that ß2-AR agonists, especially formoterol, could be a treatment for diabetic nephropathy and perhaps other forms of CKD.NEW & NOTEWORTHY Diabetic nephropathy is the most common cause of ESKD. Formoterol, a long-acting ß2-adrenergic receptor (ß2-AR) agonist, reversed diabetic nephropathy in murine models of type 1 and 2 diabetes. In humans, there was an association with protection from progression of CKD in patients with COPD, by means of ß2-AR agonist intake, compared with those without COPD. These data indicate that ß2-AR agonists, especially formoterol, could be a new treatment for diabetic nephropathy and other forms of CKD.

Novel pharmacological interventions for diabetic kidney disease.

PURPOSE OF REVIEW: The purpose of this review is to summarize the latest evidence on the prevention and progression of diabetic kidney disease (DKD), as well as novel pharmacological interventions from preclinical and early clinical studies with promising findings in the reduction of this condition's burden. RECENT FINDINGS: We will cover the latest evidence on the reduction of proteinuria and kidney function decline in DKD achieved through established renin-angiotensin-aldosterone system (RAAS) system blockade and the more recent addition of SGLT2i, nonsteroidal mineralocorticoid receptor antagonists (MRAs) and GLP1-RA, that combined will most likely integrate the mainstay for current DKD treatment. We also highlight evidence from new mechanisms of action in DKD, including other haemodynamic anti-inflammatory and antifibrotic interventions, oxidative stress modulators and cell identity and epigenetic targets. SUMMARY: Renal specific outcome trials have become more popular and are increasing the available armamentarium to diminish the progression of renal decline in patients at greater risk of end-stage kidney disease (ESKD) such as diabetic individuals. A combined pharmaceutical approach based on available rigorous studies should include RAAS blockade, SGLT2 inhibitors, nonsteroidal MRA and expectedly GLP1-RA on a personalized based-intervention. New specific trials designed to address renal outcomes will be needed for innovative therapies to conclude on their potential benefits in DKD.

Renal Metabolomics Study and Critical Pathway Validation of Shenkang Injection in the Treatment of Chronic Renal Failure.

To reveal the mechanism of Shenkang injection (SKI) in the treatment of chronic renal failure, and verify the key pathway. In this work, an untargeted metabolomics approach was performed by LC-MS coupled with multivariate statistical analysis to provide new insights into therapeutic mechanism of SKI. Hematoxylin-eosin (H&E) Staining and Immunohistochemistry were used to evaluate the effects of drug treatment, Western blot was used to verify the critical pathway. Then, a total of 44 potential biomarkers of chronic renal failure (CRF) were identified and reversed regulation, including 2,8-dihydroxypurine, 5-methoxytryptophan, uric acid, acetylcarnitine, taurine, etc. Mainly concerned with arginine and proline metabolism, purine metabolism, histidine metabolism, etc. Pathological examination showed that the renal interstitium of SKI group was significantly improved, with fewer inflammatory cells and thinner vascular walls compared with the model group. Immunohistochemical results showed that the expression of α-smooth muscle actin (α-SMA) was decreased, and the expression of E-cadherin was increased in CRF model group, and the two indicators were reversed regulation in SKI injection, indicating that the degree of fibrosis was relieved. Critical signaling pathway phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and nuclear factor-kappaB (NF-κB) protein expressions were significantly inhibited. This study was the first to employ metabolomics to elucidate the underlying mechanisms of SKI in chronic renal failure. The results would provide some support for clinical application of traditional Chinese medicines in clinic.

Effects of empagliflozin in patients with chronic kidney disease from Japan: exploratory analyses from EMPA-KIDNEY.

BACKGROUND: EMPA-KIDNEY assessed the effects of empagliflozin 10 mg once daily vs. placebo in 6609 patients with chronic kidney disease (CKD) at risk of progression, including 612 participants from Japan. METHODS: Eligibility required an estimated glomerular filtration rate (eGFR) of ≥ 20 < 45; or ≥ 45 < 90 ml/min/1.73m2 with a urinary albumin-to-creatinine ratio (uACR) of ≥ 200 mg/g. The primary outcome was a composite of kidney disease progression (end-stage kidney disease, a sustained eGFR decline to < 10 ml/min/1.73m2 or ≥ 40% from randomization, or renal death) or cardiovascular death. In post-hoc analyses, we explored the effects of empagliflozin in participants from Japan vs. non-Japan regions, including additional models assessing whether differences in treatment effects between these regions could result from differences in baseline characteristics. RESULTS: Japanese participants had higher levels of albuminuria and eGFR than those from non-Japan regions. During a median of 2.0 year follow-up, a primary outcome occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group (hazard ratio [HR], 0.72, 95% confidence interval [95%CI] 0.64-0.82; P < 0.0001). Among the participants from non-Japan regions, there were 399 vs. 494 primary outcomes (0.75, 0.66-0.86), and 33 vs. 64 (0.49, 0.32-0.75; heterogeneity p = 0.06) in Japan. Results were similar when models explicitly considered treatment interactions with diabetes status, categories of eGFR/uACR, and recruitment in Japan (heterogeneity p = 0.08). Safety outcomes were broadly comparable between the two groups, and by Japanese status. CONCLUSIONS: Empagliflozin safely reduced the risk of "kidney disease progression or cardiovascular death" in patients with CKD, with consistent effects in participants from Japan.

Safety and pharmacokinetics of SPR206 in subjects with varying degrees of renal impairment.

SPR206 is a novel polymyxin derivative with potent in vitro activity against susceptible and multidrug-resistant strains of Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Enterobacter species. SPR206 is eliminated renally. The safety, tolerability, and pharmacokinetics (PK) of SPR206 were evaluated in healthy subjects with normal renal function (Cohort 1) and subjects with varying degrees of renal impairment (RI) (Cohorts 2-4) or end-stage renal disease (ESRD) on hemodialysis (HD) (Cohort 5). Subjects in Cohorts 1-4 received a 100-mg intravenous (IV) dose of SPR206. Subjects in Cohort 5 received a 100-mg IV dose within 2 h after HD on day 1 and 1 h before HD on day 5. Safety and PK analyses included 37 subjects. Mostly mild but no serious treatment-related adverse events were reported. Systemic exposure to SPR206 increased as renal function decreased, with mean area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last) values 39% to 239% greater in subjects with RI vs healthy subjects. Mean plasma clearance (CL) of SPR206 decreased with decreasing renal function (29% to 76% lower vs healthy subjects). In subjects with ESRD, AUC0-last decreased by 51%, and CL increased by 92% for dialyzed vs nondialyzed conditions. SPR206 was excreted in urine within 12 h in healthy subjects and subjects with mild RI (Cohort 2) but was prolonged in those with moderate and severe RI (Cohorts 3 and 4, respectively). In summary, SPR206 was generally safe and well tolerated, and the PK of SPR206 was well characterized in subjects with RI.

Mineralocorticoid Receptor-Associated Mechanisms in Diabetic Kidney Disease and Clinical Significance of Mineralocorticoid Receptor Antagonists.

BACKGROUND: Diabetic kidney disease (DKD) is a common disorder with multiple serious clinical implications, including an increased risk of end-stage kidney disease (ESKD), cardiovascular complications, heart failure, onset or worsening of hypertension, and premature death. Patients with DKD frequently require dialysis or kidney transplantation to manage their ESKD. SUMMARY: Upregulation of the renin-angiotensin-aldosterone system is an important contributor to kidney disease progression, as highlighted by the results of trials evaluating angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with albuminuria. Increasing evidence suggests the existence of a multidirectional network that involves aldosterone, the mineralocorticoid receptor (MR), and the Ras-related C3 botulinum toxin substrate 1 (Rac1) as driving forces in the generation of reactive oxygen species and oxidative stress-induced injury in the initiation of interstitial nephritis and eventual fibrosis in chronic kidney disease and DKD. The MR is a key element of this triangle, as highlighted by the beneficial effect of MR antagonists in preventing or reducing aldosterone- or Rac1-related effects in basic science studies, and the improved patient outcomes observed in clinical studies. KEY MESSAGES: Aldosterone can promote kidney disease in diabetes via the MR and via MR-independent actions through Rac1. However, the MR remains a key element of this triangle, with clinical data supporting the use of MR antagonists in delaying the progression of kidney disease in diabetes.

Discontinuation of Renin-Angiotensin System Inhibitors and Clinical Outcomes in Chronic Kidney Disease: A Systemic Review and Meta-Analysis.

BACKGROUND: Discontinuation of renin-angiotensin system (RAS) inhibitors is common in patients with chronic kidney disease (CKD), and the potential danger has been reported in several studies. However, a comprehensive analysis has not been conducted. OBJECTIVES: This study sought to evaluate the effects of discontinuation of RAS inhibitors in CKD. METHOD: Relevant studies up to November 30, 2022, were identified in the PubMed, Embase, Web of Science, and Cochrane Library databases. Efficacy outcomes included the composite of all-cause mortality, cardiovascular events, and end-stage kidney disease (ESKD). Results were combined using a random-effects or fixed-effects model, and sensitivity analysis used the leave-one-out method. RESULTS: Six observational studies and one randomized clinical trial including 244,979 patients met the inclusion criteria. Pooled data demonstrated that discontinuation of RAS inhibitors was associated with an increased risk of all-cause mortality (HR 1.42, 95% CI 1.23-1.63), cardiovascular event risk (HR 1.25, 95% CI 1.17-1.22), and ESKD (HR 1.23, 95% CI 1.02-1.49). In sensitivity analyses, the risk for ESKD was reduced. Subgroup analysis showed that the risk of mortality was more pronounced in patients with eGFR above 30 mL/min/m2 and in patients with hyperkalemia-related discontinuation. In contrast, patients with eGFR below 30 mL/min/m2 were at great risk of cardiovascular events. CONCLUSIONS: The discontinuation of RAS inhibitors in patients with CKD was associated with a significantly increased risk of all-cause mortality and cardiovascular events. These data suggest that RAS inhibitors should be continued in CKD if the clinical situation allows.

Interpretation of GFR slope in untreated and treated adult Fabry patients.

Nephropathy is one of the main features of Fabry disease (FD) that leads, in untreated patients with classical mutations, to end-stage renal disease (ESRD) from the third to the fifth decade of life. The availability of a specific treatment modified the natural history of FD; in particular, it was widely reported that enzyme replacement therapy (ERT) is able to slow the progression of the disease. Regarding Fabry nephropathy, several reports have documented an elevated estimated glomerular filtration rate (eGFR) slope in untreated patients as expression of a rapid disease progression towards ESRD. Otherwise, the prompt start of treatment may be beneficial in stabilizing renal function or slowing its decline. Therefore, based on data in the literature about the effects of ERT on eGFR decline and on the evidence supporting the role of eGFR slope as a surrogate endpoint for chronic kidney disease progression, we suggest, in this 'Expert Opinion', that a treatment should be defined effective when eGFR decline is <1 ml/min/1.73 m2/year and not effective when eGFR loss remains ≥3 ml/min/1.73 m2/year (≥2.5 ml/min/1.73 m2/year in females). Moreover, practical clinical recommendations and guidance for Fabry patients suggests that a change in treatment may be appropriate if individualized therapeutic goals are not achieved. Since a dose-dependent efficacy has been demonstrated for ERT, we suggest considering a switch to a higher dose of ERT in symptomatic adult Fabry patients (ages 18-60 years) with an eGFR of 45-90 ml/min/1.73 m2 and treated with a stable dose of ERT for at least 1 year, in which a linear negative slope of eGFR of 3 ml/min/1.73 m2/year for males (2.5 ml/min/1.73 m2/year for females) was observed.

Effectiveness of renin-angiotensin-aldosterone system blockers in patients with Alport syndrome: a systematic review and meta-analysis.

BACKGROUND: Although renin-angiotensin-aldosterone system (RAAS) blockers have been considered the primary treatment for patients with Alport syndrome (AS) for a decade, there is no comprehensive review with evidence-based analysis evaluating the effectiveness of RAAS blockers in AS. METHODS: A systematic review and meta-analysis was performed of published studies that compared outcomes related to disease progression between patients with AS receiving RAAS blockers with those taking non-RAAS treatment. Outcomes were meta-analyzed using the random effects models. Cochrane risk-of-bias, Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development and Evaluation methodology (GRADE) assessment determined the certainty of evidence. RESULTS: A total of eight studies (1182 patients) were included in the analysis. Overall, the risk of bias was low to moderate. Compared with non-RAAS treatment, RAAS blockers could reduce the rate of progression to end-stage kidney disease (ESKD) [four studies; hazard ratio (HR) 0.33, 95% confidence interval (CI) 0.24-0.45; moderate certainty evidence]. After stratified by genetic types, a similar benefit was detected: male X-linked AS (XLAS) (HR 0.32, 95% CI 0.22-0.48), autosomal recessive AS (HR 0.25, 95% CI 0.10-0.62), female XLAS and autosomal dominant AS (HR 0.40, 95% CI 0.21-0.75). In addition, RAAS blockers showed a clear gradient of benefit depending on the stage of disease at the initiation of treatment. CONCLUSION: This meta-analysis suggested that RAAS blockers could be considered as a specific therapy to delay of ESKD for AS with any genetic type, especially at the early stage of the disease, and every further more-effective therapy would be advised to be applied on top of this standard of care.

Resistant hypertension in dialysis.

Hypertension is the most common finding in chronic kidney disease patients, with prevalence ranging from 60% to 90% depending on the stage and etiology of the disease. It is also a significant independent risk factor for cardiovascular disease, progression to end-stage kidney disease and mortality. According to the current guidelines, resistant hypertension is defined in the general population as uncontrolled blood pressure on three or more antihypertensive drugs in adequate doses or when patients are on four or more antihypertensive drug categories irrespective of the blood pressure control, providing that antihypertensive treatment included diuretics. The currently established definitions of resistant hypertension are not directly applicable to the end-stage kidney disease setting. The diagnosis of true resistant hypertension requires confirmation of adherence to therapy and confirmation of uncontrolled blood pressure values by ambulatory blood pressure measurement or home blood pressure measurement. In addition, the term "apparent treatment-resistant hypertension," defined as an uncontrolled blood pressure on three or more antihypertensive medication classes, or use of four or more medications regardless of blood pressure level was introduced. In this comprehensive review we focused on the definitions of hypertension, and therapeutic targets in patients on renal replacement therapy, including the limitations and biases. We discussed the issue of pathophysiology and assessment of blood pressure in the dialyzed population, management of resistant hypertension as well as available data on prevalence of apparent treatment-resistant hypertension in end-stage kidney disease. To conclude, larger sample-size and even higher quality studies about drug adherence should be conducted in the population of patients with the end-stage kidney disease who are on dialysis. It also should be determined how and when blood pressure should be measured in the group of dialysis patients. Additionally, it should be stated what the target blood pressure values in this group of patients really are. The definition of resistant hypertension in this group should be revisited, and its relationship to both subclinical and clinical endpoints should be established.

Randomized, double-blind, placebo-controlled phase 3 study of bardoxolone methyl in patients with diabetic kidney disease: design and baseline characteristics of the AYAME study.

BACKGROUND: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD), but currently available treatments do not improve kidney function or prevent the initiation of dialysis/kidney replacement therapy. A previous study demonstrated that bardoxolone methyl improves the estimated glomerular filtration rate (eGFR), but the study was prematurely terminated because of an imbalance in heart failure between treatment groups. The subsequent phase 2 TSUBAKI study demonstrated no incidence of heart failure and an improved eGFR and GFR as determined by inulin clearance in DKD patients. METHODS: This randomized, double-blind, placebo-controlled multicentre phase 3 study was designed to assess the efficacy and safety of bardoxolone methyl in DKD patients with an eGFR ≥15.0-<60.0 ml/min/1.73 m2 and a urinary albumin:creatinine ratio (UACR) ≤3500 mg/g but without risk factors for heart failure. The primary endpoint is the time to onset of a ≥30% decrease in the eGFR or ESKD. Randomized patients (1:1) have been under treatment with once-daily oral bardoxolone methyl (5, 10 or 15 mg by intrapatient dose adjustment) or placebo for at least 3 years. RESULTS: The mean age of the 1013 patients is 65.9 years, 21.5% are female, the mean eGFR is 37.84 ml/min/1.73 m2 and the median UACR is 351.80 mg/g. CONCLUSIONS: Appropriate patients are enrolled in this study. This study will investigate the long-term efficacy and safety of bardoxolone methyl in DKD patients covering a wider range of eGFR (≥15.0-<60.0 ml/min/1.73 m2) and albuminuria (≤3500 mg/g) compared with previous studies.

Functional Characteristics and Phenotypic Plasticity of CD57+PD1- CD4 T Cells and Their Relationship with Transplant Immunosuppression.

Costimulation blockade (CoB)-based immunosuppression offers the promise of improved transplantation outcomes with reduced drug toxicity. However, it is hampered by early acute rejections, mediated at least in part by differentiated, CoB-resistant T cells, such as CD57+PD1- CD4 T cells. In this study, we characterize these cells pretransplant, determine their fate posttransplant, and examine their proliferative capacity in vitro in humans. Our studies show that CD57+PD1- CD4 T cells are correlated with increasing age and CMV infection pretransplant, and persist for up to 1 y posttransplant. These cells are replication incompetent alone but proliferated in the presence of unsorted PBMCs in a contact-independent manner. When stimulated, cells sorted by CD57/PD1 status upregulate markers of activation with proliferation. Up to 85% of CD57+PD1- cells change expression of CD57/PD1 with stimulation, typically, upregulating PD1 and downregulating CD57. PD1 upregulation is accentuated in the presence of rapamycin but prevented by tacrolimus. These data support a general theory of CoB-resistant cells as Ag-experienced, costimulation-independent cells and suggest a mechanism for the synergy of belatacept and rapamycin, with increased expression of the activation marker PD1 potentiating exhaustion of CoB-resistant cells.

The effectiveness of sertraline in alleviating uremic pruritus in hemodialysis patients: a randomized clinical trial.

INTRODUCTION: Uremic pruritus (UP) is a common and distressing symptom in end stage renal disease (ESRD) patients. Many approaches have been tested to improve UP without a clear success. We aimed to assess the effect of sertraline on UP in hemodialysis (HD) patients. METHODS: This research is a double-blinded, placebo-controlled, multicentric randomized clinical trial which included sixty patients maintained on regular HD. Patients were allocated to receive sertraline 50 mg twice daily or placebo for 8 weeks. The Visual analogue scale (VAS) and the 5-D itch scale were used to assess pruritus before and after the course of treatment. RESULTS: At study end in sertraline group, there was a significant decrease from baseline findings in the VAS score (p < 0.001), and the 5-D itch scale (p < 0.001). On the other hand, in placebo group the VAS score showed a slight non-significant decrease (p = 0.469), and the 5-D scale (p = 0.584) increased from baseline measurements. The percentage of patients with severe and very severe pruritus decreased significantly in the sertraline group in both scores [(VAS score: p = 0.004), (5-D itch score: p = 0.002)] with no significant change in the placebo group [(VAS score: p = 0.739), (5-D itch scale: p = 0.763)]. There was a significant positive relation between the VAS and 5-D itch scores and serum urea with p value of 0.002 and 0.001 respectively, and serum ferritin with p value of < 0.001 with both. CONCLUSIONS: Patients treated with sertraline had a significant improvement in pruritus as compared with those who received placebo suggesting a potential role for sertraline to treat uremic pruritus in HD patients. Larger randomized clinical trials are needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05341843. First registration date: 22/04/2022.

Cardiometabolic comorbidities in autosomal dominant polycystic kidney disease: a 16-year retrospective cohort study.

BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disease and the fourth leading cause of end-stage renal disease (ESRD) requiring renal replacement therapy (RRT). Nevertheless, there is a paucity of epidemiological research examining the risk factors and survival on RRT for ADPKD. Thus, we aimed to investigate the cumulative effects of cardiometabolic comorbidities, including hypertension (HTN), type 2 diabetes mellitus (DM), and dyslipidemia (DLP) to clinical outcomes in ADPKD. METHODS: We identified 6,142 patients with ADPKD aged ≥ 20 years from 2000 to 2015 using a nationwide population-based database. HTN, DM, and DLP diagnoses before or at the time of ADPKD diagnosis and different combinations of the three diagnoses were used as the predictors for the outcomes. Survival analyses were used to estimate the adjusted mortality risk from cardiometabolic comorbidities and the risk for renal survival. RESULTS: Patients with ADPKD who developed ESRD had the higher all-cause mortality (HR, 5.14; [95% CI: 3.88-6.80]). Patients with all three of the diseases had a significantly higher risk of entering ESRD (HR:4.15, [95% CI:3.27-5.27]), followed by those with HTN and DM (HR:3.62, [95% CI:2.82-4.65]), HTN and DLP (HR:3.54, [95% CI:2.91-4.31]), and HTN alone (HR:3.10, [95% CI:2.62-3.66]) compared with those without any three cardiometabolic comorbidities. CONCLUSIONS: Our study discovered the cumulative effect of HTN, DM, and DLP on the risk of developing ESRD, which reinforces the urgency of proactive prevention of cardiometabolic comorbidities to improve renal outcomes and overall survival in ADPKD patients.

Impact of anemia treatment for left ventricular hypertrophy using long-acting erythropoietin-stimulating agents from the pre-dialysis to maintenance dialysis period in patients with chronic kidney disease, retrospective longitudinal cohort study.

BACKGROUND: Anemia in patients with chronic kidney disease (p-CKDs) may initiate or exacerbate left ventricular hypertrophy (LVH). This study aimed to determine whether treatment using long-acting erythropoietin-stimulating agents (L-ESAs) is independently associated with LVH during the pre-dialysis to maintenance dialysis period in p-CKDs. METHODS: Physical and laboratory examinations were performed 120 days before initiating dialysis in p-CKDs (baseline). To evaluate the left ventricular mass index (LVMI) after starting dialysis, the mean hemoglobin (Hb) was defined as the average at the start of dialysis and 6 months after starting dialysis. Changes in the LVMI were observed in three groups according to mean Hb levels (Hb < 10.1, 10.1 < Hb < 11.0, and Hb > 11.0 g/dL for Groups 1, 2, and 3, respectively). LVMI was evaluated using echocardiography at the pre-dialysis, initiation, and maintenance dialysis periods. RESULTS: A lower LVMI at dialysis initiation and an improvement in LVMI were detected in the highest tertile group of mean Hb (11.0 g/dl). Consequently, in the high Hb group (Hb level > 11.0 g/dl), LVMI remained low from dialysis initiation until after 6 months.The relationship between Hb and LVMI was not significant; however, a constant correlation with ß ≥ 0.4 in the absolute value was maintained. CONCLUSION: L-ESAs may correlate with Hb and LVMI after administration, independent of the baseline LVMI and Hb values. These findings have therapeutic implications in the treatment strategies for p-CKDs during the pre-dialysis to maintenance dialysis period.

UK prescribing practice of anticoagulants in patients with chronic kidney disease: a nephrology and haematology-based survey.

A survey to gain insight into anticoagulant prescribing practice in the setting of chronic kidney disease (CKD) across the UK was disseminated via renal and haematology networks. Areas of anticoagulant use included patients with venous thromboembolism (VTE), requiring thromboprophylaxis for VTE, Atrial Fibrillation (AF) and nephrotic syndrome.An online-survey was disseminated via British Haematology Society, UK Kidney Association, and Renal Pharmacy Group over a five month period. All responses were voluntary and anonymous.Among 117 responses there were 49 nephrology doctors, 47 renal pharmacists and 20 haematology clinicians. A specialist multidisciplinary team to discuss the specific anticoagulant management of these patients was only available to 3% (4/117) respondents. Renal function estimate used for anticoagulant dosing was mainly Cockcroft-Gault for pharmacists and haematology but lab-based estimates were used by nephrology doctors. Therapeutic dose of Low Molecular Weight Heparin was mostly likely to be reduced by one-third when used for VTE treatment, with the majority of units undertaking anti-Xa monitoring in CKD stage 5 and dialysis. Direct-acting Oral Anticoagulants are being used in patients with nephrotic syndrome, those with CKD stage 5 and on dialysis for VTE and AF in the absence of license in these indications.This survey highlighted the significant differences between anticoagulant prescribing in CKD between two professional specialties and marked variation between centres in anticoagulant management strategies employed for these patients. With gaps still existing in the evidence base and answers to these not expected within the next few years, development of a best-practice guideline would be warranted to support clinicians in this field.

Pharmacokinetic-pharmacodynamic modeling of the active components of Shenkang injection in rats with chronic renal failure and its protective effect on damaged renal cells.

The study aimed to explore the pharmacokinetic and pharmacodynamic alterations of the active components of Shenkang injection (i.e. hydroxy saffron yellow pigment A [HSYA], tanshinol, rheum emodin, and astragaloside IV) in rats with chronic renal failure (CRF), and establish a pharmacokinetic-pharmacodynamic model (PK-PD model) in order to provide a scientific and theoretical basis for the rational clinical use of Shenkang injection. Sprague-Dawley (SD) rats were randomly divided into a normal group, model group, and Shenkang injection group. A rat model of CRF was induced by adenine gavage and then followed by drug administration via tail vein injection. Orbital blood was collected at different timepoints and the blood concentrations of the four active components were measured by UHPLC-Q-Orbitrap HRMS. Serum levels of creatinine (Scr), urea nitrogen (BUN), and uric acid (UA) were determined using an automatic biochemical analyzer. A PK-PD model was established, and DAS 3.2.6 software was used for model fitting as well as statistical analysis. TGF-ß1 was utilized to induce normal rat kidney cells to construct a renal fibrosis model to investigate the protective effect of the pharmacological components on renal fibrosis. The pharmacokinetic analysis of hydroxy saffron yellow pigment A, tanshinol, rheum emodin, and astragaloside IV based on UHPLC-Q-Orbitrap HRMS was stable. The linear regression equations for the four active components were as follows: Y = 0.031X + 0.0091 (R2  = 0.9986) for hydroxy saffron yellow pigment A, Y = 0.0389X + 0.164 (R2  = 0.9979) for tanshinol, Y = 0.0257X + 0.0146 (R2  = 0.9973) for rheum emodin, and Y = 0.0763X + 0.0139 (R2  = 0.9993) for astragaloside IV, which indicated good linear relationships. The methodological investigation was stable, with the interday and intraday precision RSD <10%. Meanwhile, the recoveries ranged between 90% and 120%, in accordance with the requirements for in vivo analysis of drugs. Compared with the model group, the levels of Scr, BUN, and UA were significantly decreased after 20 min in the Shenkang injection group (p < 0.01). The PK-PD model showed that the four active components in the Shenkang injection group could fit well with the three effect measures (i.e. Scr, BUN, and UA), with the measured values similar to the predicted values. The cell model of renal fibrosis showed that the connective tissue growth factor and FN1 protein expression levels were significantly lower in the Shenkang injection group than those in the model group, and the cell fibrosis was improved. The established method for in vivo analysis of Shenkang injection was highly specific, with good separation of the components and simple operation. The total statistical moment could well integrate the pharmacokinetic parameters of the four active components. After treatment with Shenkang injection, all indexes in the administered group improved and showed significant inhibition of renal cell fibrosis in vitro. This study could provide scientific reference ideas for the clinical rational use of traditional Chinese medicine.

Effects of caffeic acid phenethyl ester use and inhibition of p42/44 MAP kinase signal pathway on caveolin 1 gene expression and antioxidant system in chronic renal failure model of rats.

Effects of Caffeic acid phenethyl ester (CAPE) and/or PD98059 (PD) on the gene expression of Caveolin-1 (CAV1) and reduced glutathione (GSH), malondialdehyde (MDA), copper-zinc superoxide dismutase (CuZn-SOD), and catalase (CAT) enzyme activities were investigated in an experimental chronic renal failure model in rats. Eighty Wistar rats were divided into eight groups for a 28-day study: Control, CsA (Cyclosporine A), CsA-V (CsA solvent), CsA + PD (CsA + PD98059), CsA + PD + CAPE, CsA + CAPE, CAPE-V (CAPE solvent), and PD-V (PD98059 solvent). Serum blood urea nitrogen and creatinine levels, as well as histopathological findings indicated the development of renal failure in the CsA group. Kidney GSH levels decreased while MDA levels, CuZn-SOD, and CAT activities increased significantly in the CsA group compared to control indicating oxidative stress. CAV1 gene expression significantly decreased in the CsA group compared to the control. PD98059 and CAPE applications made positive improvements in the levels of the parameters investigated. PD98059 and CAPE applications in CsA given animals increased GSH and CAV1 gene expressions and decreased CuZn-SOD and CAT levels compared to the CsA group. In conclusion, it was shown that PD98059 and CAPE could attenuate the effects of chronic renal failure, and CAV1 is suggested as a therapeutic target and the inhibition of the p44/42 MAPK pathway may be a new approach for the treatment of renal degenerations.

In vitro cytogenetic analysis of two different anti-phosphates (sevelamer hydrochloride and calcium carbonate) agents used by patients with hyperphosphatemia.

Sevelamer hydrochloride (SH) and calcium carbonate (CaCO3) are two agents included in the phosphate-binding group which are frequently prescribed in the treatment of patients with hyperphosphatemia. However, there are no satisfactory studies on the genotoxic effects of SH in vitro. This study was conducted to reveal the genotoxic and/or cytotoxic potential of these two drugs in cultured human peripheral lymphocytes. Human peripheral lymphocytes were treated with SH and CaCO3 at sublethal concentrations for 24 or 48 h for micronucleus assay and 1 h in the comet assay. CaCO3 and SH stimulated a slight increase in micronucleus formation however this increase was not significant compared to the control group. According to the findings of the comet test, only one concentration of the SH caused significant DNA damage (2 mg/ml, 48 h) whereas CaCO3 did not cause important DNA breakage. No significant oxidative damage or anti-radical effect caused by test substances was observed on the pure pBR322 plasmid DNA in a cell-free medium. Also, it was found that the drugs were devoid of mutagenic activity in the Ames test, but had a weak cytotoxic effect. Both test substances, particularly SH, significantly reduced the nuclear division index compared to the control group. In conclusion, the cytotoxic effect of SH was evident on the basis of in vitro tests and slightly higher than CaCO3.