Different Levels Of Renal Function Research Articles

#501 Evaluation of the accuracy of serum creatinine-based GFR calculations across the different levels of renal function among Filipinos

Abstract Background and Aims Chronic kidney disease (CKD) is a worldwide health concern which continues to increase in prevalence. Early studies have evaluated kidney function by measuring serum creatinine (sCr) and/or the estimated glomerular filtration rate (eGFR). To date, there are limited studies that correlate nuclear GFR scans and eGFR by equations that include the Cockroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 2021 in Asians, specifically in a Filipino population. This study aims to compare the accuracy of GFR scan results and GFR estimated from the formulas across different levels of kidney functions, age groups, gender, and co-morbidities among a Filipino subset. Method A cross-sectional study was done among 2986 patients who underwent Nuclear GFR scan in a single kidney center. Results obtained were compared to estimated GFR results. Weighted Kappa and Bland-Altman Analyses were used to test for agreement between the measured and estimated GFR results. Results Absolute GFR values derived from the three equations demonstrated moderate reliability with results from nuclear scan when intraclass correlation coefficients were calculated with CKD-EPI 2021 being the highest. When further categorized into GFR levels, there was substantial level of agreement between each equation and GFR scan, with all weighted kappa coefficients being at least 0.700 with CG having the highest result (Table 1). Furthermore, when subgroup analysis was done according to age group, gender, and comorbidities, CG was found to be the most accurate per category (Table 2). Conclusion CKD-EPI 2021 was the most accurate in the actual GFR values however we cannot fully eliminate the utility of CG due to its categorical accuracy and in monitoring the deterioration of renal function.

Therapy of Type 2 diabetes: more gliflozines and less metformin?

Metformin is a frequently used anti-diabetic drug. In addition to the well-known modulating properties on glyco-metabolic control, metformin reduces cardiovascular (CV) risk partly independently of its anti-hyperglycaemic effect. The use of 'new' anti-diabetic drugs, inhibitors of the renal Na-glucose co-transporter (SGLTs-I or 'gliflozines') and GLP-1 receptor agonists (GLP1-RAs), has further contributed to challenge the strictly 'gluco-centric' view of diabetic CV disease. Several controlled trials have demonstrated that the cardio-renal benefits of gliflozines and GLP1-RAs are present regardless of the presence of metformin as 'background' therapy. The impact on the 'cardio-renal continuum' exerted by SGLTs-I was also noted in non-diabetic patients with heart failure and reduced or preserved ventricular function and different levels of renal function. These drugs reduced re-hospitalization, CV mortality, and progression to end-stage renal disease. These clinical acquisitions, implemented by Scientific Societies, have led to a change in the therapeutic approach to diabetic cardio-renal disease. Although metformin still represents a valid therapeutic option to be offered particularly to 'naïve' diabetic patients without previous cardio-renal events, SGLTs-I and/or GLP1-RAs emerge as 'first-line' drugs in diabetic patients with previous CV events, or at high CV risk, without having to request 'on board' metformin therapy.

Application of urine C-peptide creatinine ratio in type 2 diabetic patients with different levels of renal function.

This study aims to investigate the effect of single urine C peptide/creatinine (UCPCR) in assessing the islet β Cell function of type 2 diabetes mellitus (T2DM) patients with different renal function. A total of 85 T2DM patients were recruited in this study, all the patients were assigned to one group with estimated glomerular filtration rate (eGFR)≤60 ml·min-1·1.73 m-2 and another group complicated with eGFR>60 ml·min-1·1.73 m-2. Serum creatinine, urine creatinine, serum fasting C-peptide (FCP), fasting blood glucose (FBG), glycosylated hemoglobin (HbA1C) and 24-hour urinary C-peptide (24hUCP) were measured. The modified homeostasis model assessment-islet β cell function [HOMA-islet (CP-DM)], the modified homeostasis model assessment-insulin resistance [HOMA-IR(CP)] and UCPCR were calculated. When compared with group eGFR ≤60 ml·min-1·1.73 m-2, the levels of UCPCR, FCP, the modified HOMA-IR(CP) and HOMA-islet (CP-DM) were promoted and the concentrations of HbA1C, FPG, creatinine were decreased in the patients of eGFR>60 ml·min-1·1.73 m-2 (P<0.05); FCP was uncorrelated with 24hUCP while associated with UCPCR in the patients of eGFR ≤ 60 ml·min-1·1.73 m-2; UCPCR was positively correlated with FCP and HOMA-IR(CP) in the T2DM patients with different levels of renal function; the cut-off (UCPCR ≤ 1.13 nmol/g) had 88.37% sensitivity and 95.24% specificity [95% confidence interval (CI):0.919-0.997] for identifying severe insulin deficiency in T2DM patients[area under the curve (AUC) 0.978]. UCPCR can be used to evaluate islets β Cell function in T2DM patients with different renal function status.

The Urinary Glucose Excretion by Sodium–Glucose Cotransporter 2 Inhibitor in Patients With Different Levels of Renal Function: A Systematic Review and Meta-Analysis

ObjectivePrevious evidence suggested that sodium–glucose cotransporter 2 inhibitor (SGLT2i)-mediated urinary glucose excretion (UGE) appeared to be reduced with a decrease in glomerular filtration rate. Thus, we conducted a systematic review and meta‐analysis to compare SGLT2i-mediated UGE among individuals with different levels of renal function.MethodsWe conducted systematic searches in PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrial.gov from inception to May 2021. Clinical studies of SGLT2i with reports of UGE changes in predefined different levels of renal function were included. The results were expressed as pooled effect sizes with 95% confidence interval (CI). A random-effects model was used to calculate the pooled effect sizes.ResultsIn total, eight eligible studies were included. Significant differences were observed in the post-treatment UGE level among subgroups stratified by renal function (P <0.001 for subgroup difference), which were gradually decreased along with the severity of impaired renal function. Consistently, changes in UGE before and after SGLT2i treatment were also decreased along with the severity of impaired renal function [67.52 g/day (95%CI: 55.58 to 79.47 g/day) for individuals with normal renal function, 52.41 g/day (95%CI: 38.83 to 65.99 g/day) for individuals with mild renal function impairment, 35.11 g/day (95%CI: 19.79 to 50.43 g/day) for individuals with moderate renal function impairment, and 13.53 g/day (95%CI: 7.20 to 19.86 g/day) for individuals with severe renal function impairment; P <0.001 for subgroup differences].ConclusionsSGLT2i-mediated UGE was renal function dependent, which was decreased with the extent of renal function impairment.

Population Pharmacokinetics Modeling of Vancomycin Among Chinese Infants With Normal and Augmented Renal Function.

There have been good amounts of population pharmacokinetics (PPK) models of vancomycin for Chinese pediatric patients, but none of them had a special focus on modeling infant population with different levels of renal function. Since renal function variability is prominent among infant population and the clearance (CL) of vancomycin is heavily related to renal excretion, it is important to establish precise PPK models based on individual renal function levels. We employed a PPK approach to develop three models of vancomycin in parallel for Chinese pediatric patients with normal renal function [estimated glomerular filtration rate (eGFR) between 30 and 86 ml/min/1.73 m2, Model 1], with augmented renal function (eGFR ≥ 86 ml/min/1.73 m2, Model 2), or with all levels of renal function (Model 3). Three one-compartment models with first-order elimination kinetics were established. The predictive ability of Model 1 and Model 2 among each certain population is comparable with that of Model 3 with no statistical difference. Our study revealed that among the infant population with augmented renal function, only body weight was included as a covariate, which indicated that for an infant whose eGFR ≥ 86 ml/min/1.73 m2, taking blood sample is not compulsory for predicting vancomycin blood concentration, which avoids unnecessary injury to vulnerable infants.

Comparison of the Safety and Efficacy of Direct Oral Anticoagulants and Warfarin in Atrial Fibrillation or Venous Thromboembolism in Patients with Renal Impairment: Systematic Review, Meta-Analysis and Network Meta-Analysis.

Due to the high risk of ischemic and arterial or venous bleeding events in atrial fibrillation (AF) or venous thromboembolism (VTE) patients with renal impairment (RI), selection of appropriate anticoagulant regimen is important. Therefore, we systematically reviewed and compared the safety and effects of oral anticoagulants in AF and VTE patients with RI. Eligible articles were identified through a literature search in PubMed, Embase, ClinicalTrials.gov, and the Cochrane Library for studies published between January 2008 and November 2020. Network meta-analysis was conducted with STATA 14.0 to analyze the effects and safety of each drug with regard to different levels of renal function. 15 studies including 82,931 patients (76,957 with AF and 5974 with VTE) were analyzed. Compared with those of warfarin, the risk ratios of effect and safety outcomes of apixaban were 0.70 (95% confidence interval [CI] 0.60-0.82) and 0.56 (95% CI 0.42-0.76) in AF patients and 0.33 (95% CI 0.19-0.59) and 0.95 (95% CI 0.68-1.34) in VTE patients. Apixaban had the first or second highest probability of being ranked first with respect to surface under the cumulative ranking curve (SUCRA) scores in the prevention of major bleeding events, while in the prevention of ischemic events, rivaroxaban showed a higher SUCRA score (0.78-0.92) in mild RI patients and dabigatran showed a higher SUCRA value (0.90-0.99) in moderate RI patients. In the systematic review and meta-analysis, for AF or VTE patients with RI, direct oral anticoagulants performed comparably to or better than warfarin with regard to safety and effects. The network meta-analysis indicated that for patients with mild RI, apixaban might be safer for patients with a lower risk of ischemic events, while rivaroxaban might be suitable for patients with a lower risk of bleeding events. For patients with moderate RI, apixaban could reduce the risk of ischemic events without increasing the risk of bleeding events. For AF patients with severe RI, apixaban, rivaroxaban, and warfarin showed a similar effect. These results might provide suggestions for clinical arterial and venous thrombosis prevention.

Biochemical Parameters of Diabetes Ketoacidosis in Patients with End-stage Kidney Disease and Preserved Renal Function.

Differences in biochemical parameters of diabetic ketoacidosis in patients with end-stage kidney disease (ESKD) has not been established. Accordingly, we assessed the relationship between degree of metabolic acidosis and ß-hydroxybutyrate in patients with ESKD (eGFR < 15 mL/min/1.73 m2), moderate renal failure (eGFR 15-60), or preserved renal function (eGFR > 60). This observational study included adults (18-80 years) with diabetes ketoacidosis (DKA), admitted to Emory University Hospitals between January 1, 2006 to December 31, 2016. DKA and renal stages were confirmed on admission laboratory values. Admission bicarbonate levels (13.9 ± 5 vs 13.4 ± 5.3 vs 13.8 ± 4.2 mmol/L, P = 0.7), and pH levels (7.2 ± 0.3 vs 7.2 ± 0.2 vs 7.2 ± 0.2, P = 0.8) were similar among groups. Patients with ESKD had lower mean ß-hydroxybutyrate level (4.3 ± 3.3 vs 5.6 ± 2.9 vs 5.9 ± 2.5 mmol/L, P = 0.01), but higher admission glucose (852 ± 340.4 vs 714.6 ± 253.3 mg/dL vs 518 ± 185.7 mg/dL, P < 0.01), anion gap (23.4 ± 7.6 vs 23 ± 6.9 vs 19.5 ± 4.7 mmol/L, P < 0.01), and osmolality (306 ± 20.6 vs 303.5 ± vs 293.1 ± 3.1mOsm/kg, P < 0.01) compared with patients with moderate renal failure and preserved renal function, respectively. The sensitivity of ß-hydroxybutyrate > 3 mmol/L for diagnosing DKA by bicarbonate level < 15 and <18 mmol/L was 86.9% and 72% in ESKD, 89.3% and 83.7% in moderate renal failure, and 96.2% and 88.3% in preserved renal function. In patients with ESKD, the corresponding ß-hydroxybutyrate with bicarbonate levels < 10, 10-15, <18 mmol/L were 5.5, 3.9, 3.0 mmol/L, respectively. Significant metabolic differences were found among DKA patients with different levels of renal function. In patients with ESKD, a ß-hydroxybutyrate level > 3 mmol/L may assist with confirmation of DKA diagnosis.

Efficacy and safety of urate-lowering therapy in people with kidney impairment: a GCAN-initiated literature review.

The aim was to evaluate the efficacy, defined as achieving target serum urate <6.0 mg/dl, and safety of urate-lowering therapies (ULTs) for people with gout and chronic kidney disease (CKD) stages 3-5. PubMed, The Cochrane Library and EMBASE were searched from 1 January 1959 to 31 January 2018 for studies that enrolled people with gout, who had an estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl) of <60 ml/min and exposure to allopurinol, febuxostat, probenecid, benzbromarone, lesinurad or pegloticase. All study designs other than case reports were included, except for people on dialysis, for whom we did include case reports. There were 36 reports with an analysis of efficacy and/or safety based upon renal function: allopurinol (n = 12), febuxostat (n = 10), probenecid (n = 3), benzbromarone (n = 5), lesinurad (n = 5) and pegloticase (n = 1). There were 108 reports that involved people with gout and renal impairment but did not contain any analysis on efficacy and/or safety based upon renal function: allopurinol (n = 84), febuxostat (n = 14), benzbromarone (n = 1), lesinurad (n = 3) and pegloticase (n = 6). Most studies excluded people with more severe degrees of renal impairment (eGFR or CrCl of <30 ml/min). For allopurinol, in particular, there was significant variability in the dose of drug used and the efficacy in terms of urate lowering, across all levels of renal impairment. There is a lack of evidence regarding the efficacy and/or safety of currently used ULTs according to different levels of renal function. Future studies should include patients with CKD and should report study outcomes stratified by renal function.

Efficacy and safety of dronedarone vs placebo in patients with atrial fibrillation or atrial flutter across a spectrum of renal function: post hoc analyses of the EURIDIS-ADONIS trials

Abstract Background/Introduction The use of antiarrhythmic drugs in patients with chronic kidney disease (CKD) is complex because impaired renal clearance can cause increased drug levels, and risk of intolerance or adverse events. Since CKD commonly co-occurs with atrial fibrillation/atrial flutter (AF/AFL), it is important to establish efficacy and safety for such drugs when used in AF/AFL patients with CKD. Purpose To evaluate the efficacy and safety of dronedarone in patients with AF or AFL across different levels of renal function. Methods This post hoc analysis evaluated pooled data from two multicentre, double-blind, randomised (2:1) trials of rhythm control with dronedarone 400 mg twice daily vs placebo. Primary endpoint was time to first recurrence of AF or AFL. Renal function (estimated glomerular filtration rate [eGFR]) was assessed with the CKD-Epidemiology Collaboration equation. Patients were grouped by eGFR strata. Log-rank testing and Cox regression were used to compare time to events between treatment groups. Results Most (85%) patients had mild or mild-to-moderate decrease in eGFR (Table 1). Median time to first AF recurrence was significantly longer in the dronedarone vs placebo group for all eGFR subgroups except the 30–44 mL/min group (Figure 1), where the trend was consistent; however, the small population size may have precluded meaningful analyses in this subgroup. Serious adverse events, deaths, and treatment discontinuations did not differ notably between each group irrespective of eGFR strata. Conclusions This analysis confirms the efficacy and safety of dronedarone in patients with AF across a wide spectrum of renal function. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Sanofi

MON-378 Efficacy and Safety of Romosozumab vs Alendronate Is Similar Across Different Levels of Renal Function Among Postmenopausal Women with Osteoporosis

Postmenopausal women with osteoporosis may also have renal insufficiency. We conducted a post hoc analysis of the ARCH study to determine the efficacy and safety of romosozumab (Romo) vs alendronate (ALN) among patients with different levels of baseline renal function.In ARCH, 4,093 postmenopausal women, 55–90 years old, were randomized 1:1 to receive monthly subcutaneous Romo 210 mg or weekly oral ALN 70 mg for 12 months (double-blind phase [DBP]). Eligible patients had a bone mineral density (BMD) T score of ≤ –2.5 at the total hip (TH) or femoral neck (FN) and either ≥ 1 moderate/severe vertebral fracture (VFx) or ≥ 2 mild VFx; or a T score of ≤ –2.0 at the TH or FN and either ≥ 2 moderate/severe VFx or an Fx of the proximal femur sustained 3–24 months before randomization. Pts were excluded for significantly impaired renal function (eGFR < 35 mL/min/1.73 m2, calculated using the MDRD equation). For the current analysis, patients were categorized by baseline eGFR: normal renal function (eGFR ≥ 90), mild renal insufficiency (eGFR 60–89), or moderate renal insufficiency (eGFR 30–59). The least squares mean (LSM) % change from baseline in BMD at the lumbar spine (LS), TH, and FN; incidence of new VFx; incidence of adverse events (AEs); and changes in renal function were assessed for each eGFR category at month 12 of the DBP.At baseline, 15% of patients had eGFR ≥ 90, 60% had eGFR 60–89, 24% had eGFR 30–59, and 0.3% had eGFR 15–29. In the overall patient population, LSM % change (95% CI) from baseline in BMD (Romo vs ALN) was 13.7% (13.4–14.0) vs 5.0% (4.7–5.2) for LS, 6.2% (5.9–6.4) vs 2.8% (2.7–3.0) for TH, and 4.9% (4.7–5.2) vs 1.7% (1.5–2.0) for FN (P < 0.001 at each site). Changes in BMD were similar irrespective of baseline eGFR. Among patients with eGFR ≥ 90, eGFR 60–89, and eGFR 30–59, the incidence of new VFx (Romo/ALN) was 3.3%/7.3% (relative risk reduction [RRR] = 57%; 95% CI: 1–81), 3.2%/3.9% (RRR = 19%; 95% CI: -28–49), and 3.4%/6.2% (RRR = 51%; 95% CI: 5–75), respectively. The incidences of AEs, serious AEs, and fatal AEs were similar in both treatment groups within each eGFR category as well as across eGFR categories; there was a higher incidence of positively adjudicated cardiovascular events in the Romo vs ALN group overall and across eGFR categories. One patient in the Romo group with eGFR 60–89 at baseline and 1 in the ALN group with eGFR ≥ 90 at baseline had an AE of mild hypocalcemia. Similar percentages of patients in the Romo and ALN groups had changes in renal function over 12 months of treatment.In conclusion, the efficacy and safety of Romo vs ALN was similar across different levels of renal function.

Progressive immunosenescence in diabetic chronic kidney disease

Abstract Type 2 diabetes is an important challenge given the worldwide epidemic and is the most important cause of end-stage renal disease in developed countries. It is known that patients with end-stage renal disease and advanced renal failure suffer from immunosenescence and premature T cell aging, but whether such changes develop in patients with less severe chronic kidney disease (CKD) is unclear. We investigated level of immunosenescence in 770 Patients with type 2 diabetes with different levels of renal function. Consistent with previous observations in the general population, both T and monocyte immunosenescence in diabetic patients positively correlate with age. Compared to patients with eGFR&amp;gt;60 ml/min, patients with more severe CKD showed a progressive decrease in total CD3+ T cells, but not in monocyte numbers. Immunosenescence, as defined by multiple phenotypic markers, was significantly upregulated in both CKD stage 3 and stage 4/5 patients, especially of CD8+ T cells. In age and sex-adjusted regression models, stage 3 CKD patients exhibited significantly elevated percentages of CD28−, CD127−, and CD57+ cells among CD8+ T cells when compared to patients with eGFR&amp;gt;60 ml/min. In contrast, no change was detected in monocyte subpopulations as renal function declined. Our study indicates that therapeutic approaches to prevent the emergence of immunosenescence in renal failure patients should be implanted before stage 3 CKD.

Immunosenescence in Type 2 Diabetic Patients with Chronic Renal Disease

Abstract Background Immunosenescence is an important challenge for an aging population. It is known that patients with end-stage renal disease suffer from immunosenescence and premature T cell aging but whether such changes occur in diabetic patients with less severe chronic renal disease is unclear. Methods 832 patients with type 2 diabetes with different levels of renal function were recruited in this study. Immunosenescence was analyzed by staining peripheral blood with two immunophenotyping panels and analyzed by multicolor flow cytometry. Results Out of all the 832 participants, there were 171 patients with stage 3 CKD and 46 patients with 4/5 CKD. Compared to patients with eGFR&amp;gt;60 ml/min, patients with more severe CKD showed progressive decreased total CD3+ T cell and CD4+ and CD8+ T cell, but not monocyte numbers. In addition, immunosenescence, as defined by various phenotypic markers, showed significant upregulation in both stage 3 and stage 4/5 patients. However, immunosenescence was not associated with proteinuria level nor worse glucose control. In age and sex adjusted regression models, stage 3 CKD patients already exhibited significant elevated percentages of CD28−, CD127− and CD57+ cells among CD8+ T cells when compared to patients with eGFR&amp;gt;60 ml/min. In addition, stage 3 CKD patients exhibited depressed HLA-DR and CX3CR1 expression in specific monocyte subpopulations. Conclusion Level of immunosenescence is not significantly associated with proteinuria nor glucose control in type 2 diabetes patients. Both T cell and monocyte compartment exhibit characteristics of immunosenescence during renal function decline, starting from stage 3 CKD.

Efficacy and Safety of Non-Vitamin K Anticoagulants for Atrial Fibrillation in Relation to Different Renal Function Levels: A Network Meta-Analysis.

Background We performed a network meta-analysis (NMA) comparing the efficacy (stroke or systemic embolism) and safety (major bleeding) among different non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) and renal impairment, with the aim of recommending the proper drug and the dose based on renal function. Methods We searched PubMed, EMBASE, Web of Science, and Cochrane Library with the items “dabigatran, edoxaban, apixaban, rivaroxaban, warfarin, and atrial fibrillation” through August 2019. NMA was analyzed with R (version 3.5.1, R Foundation for Statistical Computing) with the packages gemtc recalling JAGS (version 4.3.0) for the efficacy and safety of each drug with regard to different levels of renal function. NetMetaXL (version 1.6.1) and winBUGS (version 1.4.3) were used to obtain the cumulative ranking curve (SUCRA) of each drug. Result In patients with normal renal function, dabigatran150 was ranked as the most effective drug (SUCRA 0.90), followed by dabigatran110 (SUCRA 0.68), apixaban (SUCRA 0.66), and rivaroxaban (SUCRA 0.59). With regard to the safety for preventing major bleeding, there was high probability that edoxaban30 (SUCRA 0.99) ranked first, compared to dabigatran110 (SUCRA 0.78) and edoxaban60 (SUCRA 0.66). For patients with mild renal impairment, with respect to the most effective drug for preventing stroke or systemic embolism, edoxaban60 ranked first (SUCRA 0.98), in comparison with dabigatran150 (SUCRA 0.74) and apixaban (SUCRA 0.64). Possibility of ranking first for the safest drug was edoxaban30 (SUCRA 0.99), followed by dabigatran110 (SUCRA 0.70) and apixaban (SUCRA 0.69). In patients with moderate renal function, dabigatran150 (SUCRA 0.95) ranked as the most effective drug in comparison with apixaban (SUCRA 0.66). Dabigatran110 (SUCRA 0.53), rivaroxaban (SUCRA 0.51), and edoxaban60 (SUCRA 0.50) had the similar probability of ranking third. When referred to the safest drug, probability of ranking first for preventing major bleeding was edoxaban30 (SUCRA 0.98), followed by apixaban (SUCRA 0.85) and edoxaban60 (SUCRA 0.64). Conclusion In patients with AF and renal impairment and for patients with normal renal function, dabigatran 110 mg (bid) might have a better effect on the clinical results. And it does not coincide with patients taking dabigatran 110 mg with dose reduction for other factors including aged ≥75 years, renal impairment (CrCL 30–50 mL/min), gastritis, esophagitis, or gastroesophageal reflux, receiving concomitant verapamil, and so on. For patients with mild renal impairment, apixaban 5 mg (bid) would be a better choice for preventing stroke or systemic embolism and major bleeding, while apixaban 5 mg (bid) and edoxaban 60 mg (qd) were recommended for patients with moderate renal impairment. However, considering the fact of no RCTs for the head-to-head comparison, caution should be exercised over selecting each of NOACs for patients.

SAT-183 % FREE RENALASE IS ASSOCIATED WITH PROGRESSION OF CKD, AND IS AN INDEPENDENT PREDICTOR OF ALL CAUSE MORTALITY

Renalase is a secreted flavoprotein produced by a variety of tissues including the kidneys. A potent growth factor, renalase exerts pro-survival effect by biding to its cell surface receptor PMCA4b and activating various intracellular signaling pathways. In this study, we examined an association between renal function and plasma renalase levels using a new ELISA developed by our group. The unique feature of the ELISA is that its detection monoclonal antibody, m28-renalase, specifically targets the region of human renalase that binds to its cell surface receptor and initiates intracellular signaling. We also examined an association between plasma renalase levels and mortality. 267 patients with different levels of renal function were recruited. The plasma from the blood collected on the day of consent was stored at -80oC until analysis of renalase levels. Total and free renalase levels were measured using the new ELISA. Acidifying plasma samples by adding one volume of 1 N citric acid to two volumes of plasma exposes the binding site for m28-renalase on renalase protein, thus allowing measurement of total renalase proteins. By contrast, with untreated plasma samples, only the renalase proteins with naturally exposed binding sites or free renalase are measured. % free renalase is calculated by dividing free renalase by total renalase and then multiplying by 100. Bivariate analysis was performed for a significant association between covariables (GFR by CKD EPI equation, CKD stages, age, BMI, race, blood pressure, HTN, DM, medications, etc.) and renalase levels (total, free and % free renalase). All significant variables in bivariate analyses were entered in a regression model with the backward elimination. The baseline clinical characteristics of 273 patients were obtained. The range of total renalase was 4.1 to 49.4 µg/ml and that of free renalase 0.13 to 2.6 µg/ml. % free renalase ranged from 1.3 to 6%. In bivariate analysis, total renalase correlated positively with GFR (r = 0.27, p < 0.001) and negatively with CKD stages (ρ = -0.27, p < 0.001). By contrast, % free renalase correlated negatively with GFR (r = - 0.21, p = 0.001) and positively with CKD stages (ρ = 0.24, p < 0.001). No correlation was seen between GFR (or CKD stages) and free renalase. The correlation between renal function and total renalase (and % free renalase) remained statistically significant in the multivariable analysis. After adjusting for age and comorbidities, % free renalase independently predicted death at both 1 year (OR 9.2, 95% CI 1.2-73.6) and 5 years (OR 3.7, 95% CI 1.1-13.3). Free renalase also was an independent predictor of death at 5 years (OR 4.6, CI 1.14-18.5). Using the new ELISA that targets the biologically active site of renalase, we show that loss of GFR is associated with decreasing total renalase levels, a finding opposite from previous studies using commercially available ELISA assays. By contrast, % free renalase increases with loss of GFR. Both % free renalase and free renalase independently predicted mortality. Future studies should focus on understanding the factors that regulate the balance between total and free renalase and how changes in renalase levels affect survival.

Retinal and choroidal vasculature changes associated with chronic kidney disease.

Retinal and choroidal microvascular changes can be related to renal impairment in hypertension and chronic kidney disease (CKD). The study examines the association between retinochoroidal parameters and renal impairment in hypertensive, non-diabetic patients. This is a cross-sectional study on Caucasian patients with systemic arterial hypertension with different levels of renal function. All subjects were studied by blood chemistry, urine examination, microalbuminuria and blood pressure. Complete eye examination was completed with swept source optical coherence tomography (SS-OCT) and optical coherence tomography angiography (OCTA) scans of macular region. Patients were divided in groups: LowGFR and HighGFR and CKD- and CKD+, according to the value of glomerular filtrate (GFR) and albuminuria. LowGFR and CKD+ groups included patients with clinical kidney impairment. One hundred and twenty eyes of 120 hypertensive patients were evaluated. The mean retinal thickness was thinner in CKD+ versus CKD- group (p < 0.009). LowGFR and CKD+ groups showed thinner choroidal values than HighGFR (p < 0.02) and CKD- (p < 0.001) groups. OCTA showed lower density in LowGFR than in HighGFR group (p < 0.001) and in CKD+ versus CKD- group (p < 0.001). Albuminuria was inversely related to choroidal and retinal thickness measures (p < 0.001) and to the indices of superficial parafoveal (p < 0.05) and foveal (p < 0.05) vascular densities. CKD is associated with retinal thinning, eGFR and decreasing renal function with progressive reduction of choroidal and retinal vascular density. SS-OCT and OCTA documented close association between CKD and reduction of both choroidal thickness and paracentral retinal vascular density in hypertensive patients.

Pharmacokinetics of Vancomycin in Patients with Different Renal Function Levels.

There are many determinants of vancomycin clearance, but these have not been analyzed separately in populations with different levels of renal function, which could be why some important factors have been missed. The aim of our study was to compare the pharmacokinetic parameters and factors that may affect vancomycin pharmacokinetics in groups of patients with normal renal function and in those with chronic kidney failure. The study used a population pharmacokinetic modeling approach, based on plasma vancomycin concentrations and other data from 78 patients with chronic kidney failure and 32 patients with normal renal function. The model was developed using NONMEM software and validated by bootstrapping. The final model for patients with impaired kidney function was described by the following equation: CL (L/h) = 0.284 + 0.000596 x DD + 0.00194 x AST, and that for the patients with normal kidney function by: CL (L/h) = 0.0727 + 0.205 x FIB. If our results are confirmed by new studies on two similar populations, these factors could be considered when dosing vancomycin in patients with chronically damaged kidneys, as well as in patients with normal kidneys who frequently require high doses of vancomycin.

The intact nephron hypothesis as a model for renal drug handling.

The intact nephron hypothesis (INH) states that impaired renal function results from a reduction in the number of complete (intact) nephrons. Under this model, renal drug clearance is assumed to be a linear function of glomerular filtration while tubular handling is ignored. The aims of this study were to systematically review published studies designed to test the INH and to assess the strength of the study designs used. A systematic literature search was conducted in MEDLINE, EMBASE and Google Scholar. Studies specifically designed to understand the relationship between glomerular and tubular function across different levels of renal function were included. Studies that found a linear relationship between GFR and tubular clearance were deemed to support the INH while studies that found a non-linear relationship did not support the INH. Study design was accessed using a bespoke strength of evidence score. Thirty studies met the criteria for inclusion. Of these, 24 did not support the INH. Studies that did not support the INH used methods for measuring tubular clearance that were more robust and included subjects with a wider range of GFR values than studies that supported the INH. Our results suggest that the INH may not be a suitable general model for renal drug handling, particularly for drugs that are eliminated by tubular mechanisms. Further studies to assess the clinical importance of a non-linear relationship between drug clearance and GFR are warranted.

Association of Renal Function and Direct-Acting Antiviral Agents for HCV: A Network Meta-Analysis.

The effectiveness and safety of direct-acting antiviral agents (DAAs) in hepatitis C virus (HCV) patients with renal insufficiency remain controversial. Therefore, this network meta-analysis aims to assess effectiveness and safety of DAAs in populations with different renal function. The pooled data were obtained from Cochrane Library, EMBASE, PubMed, and Web of Science. Thirteen studies recruited 6884 patients with hepatitis C infection and reported their outcomes in relation to different levels of renal function after treatment with DAAs. The results showed no difference in the virologic responses among patients with different renal function. Regarding safety, whereas in patients without chronic kidney disease (CKD) or with early CKD DAAs were associated with a risk ratio (RR) of 0.14 (95% confidence interval (CI), 0.04 to 0.43) for renal disorder, increased risk of renal function deterioration was found in advanced-CKD patients, though this effect may be related to the natural course of advanced CKD. Similarly, patients without CKD or with early CKD showed a lower risk of anemia (RR, 0.34; 95% CI, 0.20 to 0.57) and discontinuation (RR, 0.41; 95% CI, 0.39 to 0.56) than patients with advanced CKD. The efficacy of DAAs for HCV treatment was comparable in patients with advanced CKD and in those with early CKD or without CKD. However, the safety of DAAs should be verified in future studies.

Levels of Endocan, Angiopoietin-2, and Hypoxia-Inducible Factor-1a in Patients with Autosomal Dominant Polycystic Kidney Disease and Different Levels of Renal Function

Background: Endothelial dysfunction leading to unbalanced vasoconstriction and ischemia of renal parenchyma is increasingly proposed as an alternative pathway of renal damage in autosomal dominant polycystic kidney disease (ADPKD). However, human studies investigating the evolution of such phenomena are limited. This study investigated the levels of emerging biomarkers of endothelial function, angiogenesis and hypoxia, in ADPKD patients with different renal function. Methods: The study population consisted of three groups: 26 ADPKD patients with impaired renal function (Group A; estimated glomerular filtration rate [eGFR] 45–70 mL/min/1.73 m²), 26 ADPKD patients with preserved renal function (Group B; eGFR >70 mL/min/1.73 m²), and 26 age- and sex-matched controls with no history of renal disease. Circulating levels of endocan (endothelial cell-specific molecule-1) angiopoietin-2, and hypoxia-inducible factor-1a (HIF-1a) were determined by enzyme-linked immunosorbent assay techniques. Results: Patients in Group A had significantly higher levels of endocan (7.17 ± 0.43 ng/mL), angiopoietin-2 (5,595.43 ± 3,390), and HIF-1a (163.68 ± 37.84 pg/mL) compared to patients in Group B (6.86 ± 0.59 ng/mL, p = 0.017, 3,854.41 ± 3,014.30, p = 0.018, 136.84 ± 42.10 pg/mL, p = 0.019 respectively) or controls (4.83 ± 0.69 ng/mL, 1,069 ± 427.88 pg/mL, 70.20 ± 17.49 pg/mL, p < 0.001 for all comparisons). Of note, patients in Group B had also higher levels of all markers compared to controls (p < 0.001) despite having similar renal function. In correlation analyses within ADPKD patients, we noted strong correlations of all studied markers with asymmetric dimethylarginine (ADMA; endocan r = 0.908, p < 0.001, angiopoietin-2 r = 0.983, p < 0.001 and HIF-1a r = 0.998, p < 0.001), and only weak or modest correlations with eGFR. Conclusions: This study suggests that endothelial dysfunction causing microcirculatory changes, linked to angiogenesis and hypoxia, may come early in the course of ADPKD and could be a key regulator of renal injury progression.

Valganciclovir Pharmacokinetics in Patients Receiving Oral Prophylaxis Following Kidney Transplantation and Model-Based Predictions of Optimal Dosing Regimens.

Valganciclovir is used as oral prophylaxis for cytomegalovirus (CMV) infection in kidney transplant recipients. However, limited pharmacokinetic data exist to guide dosing in this patient group. This study aimed to describe the population pharmacokinetics of valganciclovir in a large sample of kidney transplant recipients and predict optimal dosing based on Monte Carlo simulations. Therapeutic drug monitoring (TDM) data from adult kidney transplant recipients who received valganciclovir prophylaxis during a 10-year study period were collected retrospectively. A non-parametric pharmacokinetic analysis and Monte Carlo simulations to determine the probabilities of reaching an area under the drug concentration-time curve (AUC) target of 40-50mg·h/L with various dosing regimens at different levels of renal function were conducted using the Pmetrics™ package for R. This study included 792 ganciclovir concentration measurements derived from 97 patients. A one-compartment oral absorption model best described the data. The final covariate model was as follows: CL(ganciclovir)=TVCL×(CLCR/51)0.75, where CL is the clearance, TVCL is the typical value of ganciclovir clearance, creatinine clearance (CLCR) according to the Cockcroft-Gaultt equation and 51 is the mean CLCR determined in the study. In the simulations, the probability of reaching the targeted AUC was insufficient when using the recommended dosing regimens for prophylaxis, especially in patients with impaired renal function at CLCR<50mL/min. Higher doses of valganciclovir corrected to renal function are suggested for use as oral prophylaxis for CMV infection in kidney transplant recipients. Further study is required to establish TDM targets to ensure adequate drug concentrations while avoiding potentially toxic drug exposures.