Decline In Creatinine Clearance Research Articles

Abstract P127: Protective Effects Of Protocatechuic Acid In Murine Model Of UUO-induced Renal Injury

Chronic kidney disease (CKD) is a global public health problem, affecting millions of people worldwide. CKD can result from obstructive nephropathy; a condition that arises from urinary flow obstruction in the kidneys, leading to renal inflammation and injury. Protocatechuic acid (PCA) is a natural phenolic compound that showed a promising protective effect in cardiovascular diseases. In the current study, we investigated the reno-protective effects of PCA in mice model of unilateral ureteral obstruction (UUO). Male C57BL/6J mice (10-12 weeks old) were divided into 4 groups (n=6-8/group). Sham control, Sham/P (sham plus PCA (50 mg/kg IP daily for two weeks), UUO, and UUO plus PCA. Induction of UUO significantly decreased creatinine clearance (CrCl) and increased pulse wave velocity (PWV), a marker of arterial stiffness, relative to sham control (CrCl; sham control: 60.6 ± 14 vs. UUO: 24.5 ± 6.0 ml/day and PWV; sham control: 1.58 ± 0.1 vs. UUO: 3.35 ± 0.22 m/s). Immuno-histochemical analysis revealed that KIM-1 expression, a marker of tubular injury, was elevated in UUO mice vs. sham control and PCA reduced this elevation, however there was no significance difference in urinary KIM-1 excretion. Moreover, UUO significantly increased renal oxidative stress and inflammation as evidenced by elevation in renal TBARs, IL-6, active caspase-1 and active MMP2 compared to sham control (TBARs; sham control: 8.3 ± 0.9 vs. UUO: 30.5 ± 3.33 nmol/mg protein, renal IL-6; sham control: 1 ± 0.07 vs. UUO: 24.35 ± 8.55 pg/mg protein, active caspase-1; sham control: 1.7 x 10 3 ± 95 vs. UUO: 2.79 x 10 3 ± 145 cpm/μg protein and MMP2; sham control: 1.6 ± 0.4 vs. UUO: 6 ± 0.6 ng/μg protein). PCA treatment significantly improved the UUO-induced decline in creatinine clearance (52.5 ± 10.2 ml/day) and attenuated UUO-induced elevation in renal PWV (1.95 ± 0.1 m/s). Furthermore, PCA treatment significantly decreased renal TBARs (5.2 ± 1.12 nmol/mg protein), IL-6 (5.39 ± 1.4 pg/mg protein) and active MMP2 (1.1 ± 0.3 ng/μg protein) in UUO-induced renal injury. Collectively, these data suggests that PCA provides renal protection in murine model of UUO via reduction of renal oxidative stress, inflammation and fibrosis.

#5231 INCREMENTAL PERITONEAL DIALYSIS VERSUS CONSERVATIVE MANAGEMENT IN PATIENTS WITH ESRD

Abstract Background and Aims At its start, Peritoneal dialysis (PD) was implemented only in advanced renal disease with a myriad of symptoms and signs. However, many subsequent literatures have highlighted possible benefits of early rather than late start of PD. Nevertheless, when to start PD has been a matter of controversy. This debate has created a new era of starting dialysis early during the course of the disease, in a small dose that was termed ‘incremental’ dialysis. By this modality, the dose of PD, is low at the initiation of RRT, and could be progressively increased over time in parallel with the reduction of RKF. Although incremental dialysis is growing worldwide, there has been no substantial agreement on the benefits of this approach. Moreover, the few available observational studies have compared incremental versus full-dose PD, with controversial results. On the other hand, studies comparing incremental dialysis with the conservative management for non-symptomatic ESRD patients are mostly deficient in the published literature. The present work is a retrospective, case-control, longitudinal study, aimed to evaluate the adequacy of incremental peritoneal dialysis as a modality of renal replacement therapy in ESRD patients, and whether it adds superior benefits over the conservative and the standard peritoneal dialysis (STPD) managements. Method Data were collected retrospectively from Complesso Integrato Columbus Policlinico Gemelli, nephrology and dialysis unit archives. The study comprising three groups: first included 23 patients who were treated with IPD and second group included 30 patients who were managed with the standard dose of PD (STPD), and a third group include 19 ESRD patients who had GFR values of < 15ml/min and were off dialysis and received only conservative treatment. The collected data for each patient included demographic, clinical assessment (volume excess and nutritional state), pharmacological data, laboratory records (Hb concentration, and sodium, potassium, phosphorus), creatinine clearance and rate of hospitalization, in addition to dialysis regimen and rate of dialysis related infection in IPD and STPD patients, data from these patients were collected at the baseline (time just before starting PD), and every 6 months for 24 months or whenever there is cessation of PD, whichever occurs first. Results In the present study all IPD group patients started PD with increment dose 1 or 2 exchanges per day, with a solution volume 1.5 to 2 L/ exchange for 8 to 16 hours/day. Data analysis revealed improvement in the nutritional state, a better control of the blood electrolyte and body volume in IPD and STPD groups while they deteriorated significantly in the conservative group (P = 0.005, P = 0.001 & P = 0.001, respectively). Dialysis groups succeed in maintain the Hb level within target level with smaller dose of ESA therapy and also ESA Resistive Index (ERI) decreased in this groups while it significantly increased in the conservative group (P1 = 0.019).There was no statistically significant differences between the rate of decline of creatinine clearance between the patients on conservative, those on IPD and STPD (P = 0.295), Also there was no statistically significant difference in the rate of hospitalization between study groups (P = 0.69).Those who had a mean creatinine clearance (CrCl) more than 9.4±2.8 ml/min/1.73m2 could be managed with one exchange to achieve the target Kt/V, a mean CrCl of less than 3.6±0.8 ml/min/1.73m2 failed to reach adequacy even with two exchanges a day and needed to be transferred to full dose while those with a mean CrCl in between the above values could only achieve Kt/V above 1.7 with two exchanges per day. Conclusion Incremental peritoneal dialysis, a rapidly growing new modality, is superior to the conservative treatment in patients with end-stage renal disease that can be adequately applied to patients with a GFR of 4 ml/min or more without adding the burden of full dose dialysis.

Protein restriction for diabetic kidney disease.

Diabetic kidney disease (DKD) continues to be the leading cause of kidney failure across the world. For decades dietary protein restriction has been proposed for patients with DKD with the aim to retard the progression of chronic kidney disease (CKD) towards kidney failure. However, the relative benefits and harms of dietary protein restriction for slowing the progression of DKD have not been addressed. To determine the efficacy and safety of low protein diets (LPD) (0.6 to 0.8 g/kg/day) in preventing the progression of CKD towards kidney failure and in reducing the incidence of kidney failure and death (any cause) in adult patients with DKD. Moreover, the effect of LPD on adverse events (e.g. malnutrition, hyperglycaemic events, or health-related quality of life (HRQoL)) and compliance were also evaluated. We searched the Cochrane Kidney and Transplant Register of Studies up to 17 November 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. We included randomised controlled trials (RCTs) or quasi-RCTs in which adults with DKD not on dialysis were randomised to receive either a LPD (0.6 to 0.8 g/kg/day) or a usual or unrestricted protein diet (UPD) (≥ 1.0 g/kg/day) for at least 12 months. Two authors independently selected studies and extracted data. Summary estimates of effect were obtained using a random-effects model. Results were summarised as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) or standardised MD (SMD) with 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We identified eight studies involving 486 participants with DKD. The prescribed protein intake in the intervention groups ranged from 0.6 to 0.8 g/kg/day. The prescribed protein intake in the control groups was ≥ 1.0 g/kg/day, or a calculated protein intake ≥ 1.0 g/kg/day if data on prescribed protein intake were not provided. The mean duration of the interventions was two years (ranging from one to five years). Risks of bias in most of the included studies were high or unclear, most notably for allocation concealment, performance and detection bias. All studies were considered to be at high risk for performance bias due to the nature of the interventions. Most studies were not designed to examine death or kidney failure. In low certainty evidence, a LPD may have little or no effect on death (5 studies, 358 participants: RR 0.38, 95% CI 0.10 to 1.44; I² = 0%), and the number of participants who reached kidney failure (4 studies, 287 participants: RR 1.16, 95% CI 0.38 to 3.59; I² = 0%). Compared to a usual or unrestricted protein intake, it remains uncertain whether a LPD slows the decline of glomerular filtration rate over time (7 studies, 367 participants: MD -0.73 mL/min/1.73 m²/year, 95% CI -2.3 to 0.83; I² = 53%; very low certainty evidence). It is also uncertain whether the restriction of dietary protein intake impacts on the annual decline in creatinine clearance (3 studies, 203 participants: MD -2.39 mL/min/year, 95% CI -5.87 to 1.08; I² = 53%). There was only one study reporting 24-hour urinary protein excretion. In very low certainty evidence, a LPD had uncertain effects on the annual change in proteinuria (1 study, 80 participants: MD 0.90 g/24 hours, 95% CI 0.49 to 1.31). There was no evidence of malnutrition in seven studies, while one study noted this condition in the LPD group. Participant compliance with a LPD was unsatisfactory in nearly half of the studies. One study reported LPD had no effect on HRQoL. No studies reported hyperglycaemic events. Dietary protein restriction has uncertain effects on changes in kidney function over time. However, it may make little difference to the risk of death and kidney failure. Questions remain about protein intake levels and compliance with protein-restricted diets. There are limited data on HRQoL and adverse effects such as nutritional measures and hyperglycaemic events. Large-scale pragmatic RCTs with sufficient follow-up are required for different stages of CKD.

A Risk Model to Predict the Longitudinal Decline in Creatinine Clearance Among Patients with Precursor Plasma Cell Dyscrasia with Baseline Chronic Kidney Failure

Monoclonal Gammopathy of Unknown Significance (MGUS) is characterized as an age-dependent condition that presents with circulating monoclonal protein originating from the clonal proliferation of plasma cells in bone marrow without overt renal failure. However, these proteins have potentials to exert stress on Glomeruli, proximal or distal tubular cells through activation of TOLL-like receptors resulted from excessive endocytosis of light chain proteins, leading to subclinical renal pathologies. This phenomenon lead to forming a new clinicopathological entity named Monoclonal Gammopathy of Renal Significance (MGRS) and can be more pronounced in patients with marginal renal function due to other causes. Importantly, the establishment of MGRS diagnosis is based on renal biopsy which is avoided frequently due to its invasive nature, therefore its overall incidence remains to be defined. Here we aim to define a risk model to predict the rate of worsening renal function in patients with Chronic Kidney Disease (CKD) who have simultaneous MGUS. Methods: To define the impact of circulating monoclonal protein on natural course of CKD progression we conducted a retrospective study of CKD patients with MGUS vs. CKD patients without MGUS. Primary end point of the study was Time to End Stage Renal Disease (TTESRD) measured from the date of diagnosis of CKD to the date of diagnosis of ESRD and was censored at the date of last follow-up for those without ESRD with death as competing risk. The Fine and Gray method was used for comparisons of cumulative incidence of ESRD between groups. The effect of important factors on TTESRD was further evaluated using multivariable Fine and Gray method. Survivor distribution was estimated using Kaplan-Meier methods and the difference of OS between/among groups was examined by log-rank test. The difference of continuous variable (age) between group was examined using T-test and the association between two categorical variables was examined using Chi-square test. CKD stages is defined by Glomerular Filtration Rate (GFR) into classic 5 categories as explained before. The rate of stage progression was analyzed as secondary end point. Results: Patients without valid data (age, date of diagnosis, invalid follow-up data) were excluded for the statistical analysis. The final analysis set included 626 patients with MGUS and CKD and 15337 patients with CKD but without known MGUS. The median follow up time was 19.7 months (range: 0.03, 128). The distribution of CKD stage and other risk factors at both cohorts are illustrated in Table-1. There was significant difference of time-to-ESRD comparing the patients who had CKD alone to patients who had both CKD and MGUS (p = 0.037) in the univariate analysis. After controlling the effects of age, gender, race, CKD stage, diabetes and hypertension, there was still marginally significant difference of TTESRD, comparing the patients who had CKD alone to patients who had both CKD and MGUS (p = 0.056). Specifically, the hazard of having ESRD for patients who had CKD without MGUS was 1.64 times (95% CI: 0.99, 2.72) of the hazard of having ESRD for patients who had CKD and MGUS (see Figure-1). The CKD stage advancement according to MGUS was analyzes as the secondary end-point of the study. The CKD stage at baseline was compared to the CKD stage at year 1 and year 5 during follow-up. The progression by stage was 28.5% at year 1 for patients without MGUS vs. 29.3% for those with MGUS (p = 0.73). The progression by stage was 38.7% at year 5 for patients without MGUS vs. 39.4 % for those with MGUS (p = 0.89).There was no statistically significant difference between median OS for CKD patients with or without MGUS. Conclusion: Here we presented the data of around 16,000 CKD pts based on the MGUS diagnosis in 19 years time span and we could not detect any higher trend for CKD pts with MGUS to develop ESRD or move to higher CKD stage. These data can suggest MGRS forms a quite thin slice of the whole MGUS population. Assessing finding of this study in a larger national database is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Neoadjuvant Chemotherapy with Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Patients with Muscle-invasive Bladder Cancer: A Retrospective Age-stratified Analysis on Safety and Efficacy

BackgroundThe standard of care (SOC) for muscle-invasive bladder cancer (MIBC) includes cisplatin-based combination chemotherapy in the neoadjuvant setting followed by radical cystectomy. Older patients often do not receive SOC due to perceived toxicity concerns despite guideline-directed recommendations. ObjectiveTo characterize the safety and efficacy of neoadjuvant accelerated methotrexate, vinblastine, adriamycin, and cisplatin (aMVAC) in MIBC patients as a function of age. Design, setting, and participantsA retrospective analysis was conducted in 186 MIBC patients treated at Fox Chase Cancer Center between January 1, 2002 and December 31, 2018. Adults with histologically proven muscle-invasive urothelial cancer were eligible. The exclusion criteria included nonurothelial histology, lack of muscularis propria invasion, and primary upper tract or metastatic disease. InterventionNeoadjuvant chemotherapy with aMVAC. Outcome measurements and statistical analysisPatients were stratified by age (<65, 65–74, and >75 yr old). Renal function was assessed at baseline and at time points after treatment. Clinicopathologic variables were compared between age groups to determine efficacy. Results and limitationsThere were no statistically significant differences in dose reductions, treatment interruptions, time to surgery, or adverse events when patients were stratified by age in univariate and multivariate analyses. Full safety data were not available due to the retrospective nature of the study. Baseline renal function was significantly worse among older patients, and the percent decline in creatinine clearance was greater with older age. We found comparable efficacy of aMVAC regardless of age. ConclusionsAccelerated MVAC was safe and demonstrated efficacy in MIBC irrespective of age in this single-center, retrospective study. Careful selection based on clinical variables, and not age, should identify patients able to receive neoadjuvant chemotherapy. Patient summaryWe examined the feasibility of the standard cisplatin-based chemotherapy regimen given prior to surgery in patients with muscle-invasive bladder cancer. Elderly patients experienced a greater decline in kidney function with treatment but not more complications than younger patients and tolerated therapy with minimal dose changes, resulting in benefit regardless of age.

Kidney function in tenofovir disoproxil fumarate-based oral pre-exposure prophylaxis users: a systematic review and meta-analysis of published literature and a multi-country meta-analysis of individual participant data.

SummaryBackgroundPrevious WHO guidance on tenofovir disoproxil fumarate-based oral pre-exposure prophylaxis (PrEP) suggests measuring creatinine levels at PrEP initiation and regularly afterwards, which might represent barriers to PrEP implementation and uptake. We aimed to systematically review published literature on kidney toxicity among tenofovir disoproxil fumarate-based oral PrEP users and conducted an individual participant data meta-analysis (IPDMA) on kidney function among PrEP users in a global implementation project dataset.MethodsIn this systematic review and meta-analysis we searched PubMed up to June 30, 2021, for randomised controlled trials (RCTs) or cohort studies that reported on graded kidney-related adverse events among oral PrEP users (tenofovir disoproxil fumarate-based PrEP alone or in combination with emtricitabine or lamivudine). We extracted summary data and conducted meta-analyses with random-effects models to estimate relative risks of grade 1 and higher and grade 2 and higher kidney-related adverse events, measured by elevated serum creatinine or decline in estimated creatinine clearance or estimated glomerular filtration rate. The IPDMA included (largely unpublished) individual participant data from 17 PrEP implementation projects and two RCTs. Estimated baseline creatinine clearance and creatinine clearance change after initiation were described by age, gender, and comorbidities. We used random-effects regressions to estimate the risk in decline of creatinine clearance to less than 60 mL/min.FindingsWe identified 62 unique records and included 17 articles reporting on 11 RCTs with 13 523 participants in meta-analyses. PrEP use was associated with increased risk of grade 1 and higher kidney adverse events (pooled odds ratio [OR] 1·49, 95% CI 1·22–1·81; I2=25%) and grade 2 and higher events (OR 1·75, 0·68–4·49; I2=0%), although the grade 2 and higher association was not statistically significant and events were rare (13 out of 6764 in the intervention group vs six out of 6782 in the control group). The IPDMA included 18 676 individuals from 15 countries (1453 [7·8%] from RCTs) and 79 (0·42%) had a baseline estimated creatinine clearance of less than 60 mL/min (increasing proportions with increasing age). Longitudinal analyses included 14 368 PrEP users and 349 (2·43%) individuals had a decline to less than 60 mL/min creatinine clearance, with higher risks associated with increasing age and baseline creatinine clearance of 60·00–89·99 mL/min (adjusted hazard ratio [aHR] 8·49, 95% CI 6·44–11·20) and less than 60 mL/min (aHR 20·83, 12·83–33·82).InterpretationRCTs suggest that risks of kidney-related adverse events among tenofovir disoproxil fumarate-based oral PrEP users are increased but generally mild and small. Our global PrEP user analysis found varying risks by age and baseline creatinine clearance. Kidney function screening and monitoring might focus on older individuals, those with baseline creatinine clearance of less than 90 mL/min, and those with kidney-related comorbidities. Less frequent or optional screening among younger individuals without kidney-related comorbidities may reduce barriers to PrEP implementation and use.FundingUnitaid, Bill & Melinda Gates Foundation, WHO.

3-year Treatment of Tenofovir Alafenamide vs. Tenofovir Disoproxil Fumarate for Chronic HBV Infection in China.

Background and AimsTenofovir alafenamide (TAF) has similar efficacy to tenofovir disoproxil fumarate (TDF) but with improved renal and bone safety in chronic hepatitis B patients studied outside of China. We report 3-year results from two phase 3 studies with TAF in China (Clinicaltrials.gov: NCT02836249 and NCT02836236).MethodsChinese hepatitis B e antigen (HBeAg)-positive and -negative chronic hepatitis B patients with viremia and elevated alanine aminotransferase were randomized 2:1 to TAF or TDF treatment groups and treated in a double-blind fashion for 144 weeks (3 years). Efficacy responses were assessed by individual study while safety was assessed by a pooled analysis.ResultsOf the 334 patients (180 HBeAg-positive and 154 HBeAg-negative) randomized and treated, baseline characteristics were similar between groups. The overall mean age was 38 years and 73% were male. The mean HBV DNA was 6.4 log10 IU/mL. The median alanine aminotransferase was 88 U/L, and 37% had a history of antiviral use. At week 144, the proportion with HBV DNA <29 IU/mL was similar among the two groups, with TAF at 83% vs. TDF at 79%, and TAF at 93% vs. TDF at 92% for the HBeAg-positive and -negative patients, respectively. In each study, higher proportions of TAF than TDF patients showed normalized alanine aminotransferase (via the American Association for the Study of Liver Diseases and the China criteria) and showed loss of HBsAg; meanwhile, the HBeAg seroconversion rates were similar. Treatment was well-tolerated among the TAF patients, who showed a smaller median decline in creatinine clearance (−0.4 vs. −3.2 mL/min; p=0.014) and less percentage change in bone mineral density vs. TDF at hip (−0.95% vs. −1.93%) and spine (+0.35% vs. −1.40%).ConclusionsIn chronic hepatitis B patients from China, TAF treatment provided efficacy similar to TDF but with better renal and bone safety at 3 years.

Kidney Function in Oral Pre-Exposure Prophylaxis Users: A Systematic Literature Review and Individual Patient Data Meta-Analysis

Background: Previous World Health Organization (WHO) guidance on tenofovir disoproxil fumarate (TDF)-based oral pre-exposure prophylaxis (PrEP) suggests measuring creatinine levels at PrEP initiation and regularly afterwards. Creatinine screening may represent barriers to PrEP implementation and uptake. We systematically reviewed published literature on renal toxicity among PrEP users and conducted an individual patient data meta-analysis (IPDMA) on kidney function among PrEP users in a global data set. Methods: Meta-analyses were conducted on published data to estimate pooled relative risks of grade 1+ and 2+ kidney-related adverse events among PrEP users. The IPDMA included data on PrEP users from 19 PrEP programmes. Estimated creatinine clearance at baseline and change in creatinine clearance after PrEP initiation were described by age, gender, and comorbidities. Random-effects regressions estimated risk in decline in creatinine clearance to <60ml/min. Findings: Eleven randomised controlled trials on oral PrEP were identified in the literature review. Pooled odds ratio (OR) for grade 1+ and grade 2+ renal adverse events was 1.51 (95% confidence interval [CI]=1.17-1.94) and 2.57 [0.97-6.77], respectively. The IPDMA included 18,676 individuals from 15 countries and 0.42% had abnormal baseline estimated creatinine clearance (<60ml/min) (increasing proportions with increasing age). Longitudinal analyses included 14,368 PrEP users and 2.43% experienced a decline to <60ml/min creatine clearance, with higher risk associated with increasing age and a baseline creatinine clearance of 60-89.99ml/min (adjusted hazard ratio [HR]=8.06 [6.44-11.2]) and <60ml/min (aHR=20.8 [12.8-33.8]). Interpretation: Few people screened for TDF-based oral PrEP had a <60ml/min creatinine clearance and renal adverse evets were rare. Older age and baseline creatinine clearance of <90ml/min were associated with clinically significant declines in creatinine clearance. Less frequent or optional screening among younger individuals without kidney-related comorbidities may be appropriate and may reduce barriers to PrEP implementation and use. Funding Information: Unitaid, Bill & Melinda Gates Foundation, WHO Declaration of Interests: The authors declare no conflict of interests.

Renoprotective Effects of a Novel Receptor-Interacting Protein Kinase 2 Inhibitor, AS3334034, in Uninephrectomized Adriamycin-Induced Chronic Kidney Disease Rats.

Renal inflammation is a final common pathway of chronic kidney disease (CKD), and its progression can be used to effectively gauge the degree of renal dysfunction. Inflammatory mechanisms contribute to glomerulosclerosis and tubulointerstitial fibrosis, which are hallmarks of CKD leading to end-stage renal disease. Receptor-interacting protein kinase 2 (RIP2) is largely committed to nucleotide-binding oligomerization domain signaling as a direct effector and transmits nuclear factor-κB (NF-κB)-mediated proinflammatory cytokine production. In the present study, we hypothesized that if inflammation via RIP2 and NF-κB signaling plays an important role in renal failure, then the anti-inflammatory effect of RIP2 inhibitors should be effective in improving CKD. To determine its pharmacologic potency, we investigated the renoprotective properties of the novel RIP2 inhibitor AS3334034 [7-methoxy-6-(2-methylpropane-2-sulfonyl)-N-(4-methyl-1H-pyrazol-3-yl)quinolin-4-amine] in uninephrectomized adriamycin-induced CKD rats. Six weeks' repeated administration of AS3334034 (10 mg/kg, once daily) significantly reduced urinary protein excretion and prevented the development of glomerulosclerosis and tubulointerstitial fibrosis. In addition, AS3334034 showed beneficial effects on renal function, as demonstrated by a decrease in levels of plasma creatinine and blood urea nitrogen and attenuation of a decline in creatinine clearance. Furthermore, AS3334034 significantly attenuated inflammation, renal apoptosis, and glomerular podocyte loss. These results suggest that the RIP2 inhibitor AS3334034 suppresses the progression of chronic renal failure via an anti-inflammatory effect and is therefore potentially useful in treating patients with CKD. SIGNIFICANCE STATEMENT: The receptor-interacting protein kinase 2 (RIP2) inhibitor AS3334034 suppresses the progression of chronic renal failure via an anti-inflammatory effect, suggesting that the nucleotide-binding oligomerization domain-RIP2 axis might play a crucial role in the pathogenesis of inflammatory kidney diseases. AS3334034 is expected to be potentially useful in the treatment of patients with chronic kidney disease.

El continuo cardiorrenal: una propuesta para la prevención de las enfermedades cardiovasculares y renales

Cardiovascular risk factors such as arterial hypertension, type 2 diabetes mellitus (DM2) and dyslipidemia are commonly involved with chronic kidney disease (CKD) and its contribution to long-term cardiovascular morbidity. Diffuse endothelial dysfunction and atherosclerosis are believed to be part of the common pathophysiology in diabetic and non-diabetic CKD, particularly in the elderly. Age is the main determinant of glomerular filtration rate (GFR) and effective renal plasma flow and has been reported that the presence of hypertension at baseline enhances the yearly decline in creatinine clearance. Dyslipidemia may directly affect the kidney by causing deleterious renal lipid disturbances (renal lipotoxicity), as well as indirectly through systemic inflammation and oxidative stress, vascular injury, hormones change and other signaling molecules with renal action. Several cross-sectional studies found that impaired glucose tolerance, as well as the presence of left ventricular hypertrophy, was associated with an increase in the slope of the inverse relationship between age and GFR in subjects with never-treated essential hypertension. Most of the drugs used to reduce the burden of risk factor on cardiovascular disease also benefit the renal function. So, we propose the cardiorenal continuum as a preventive strategy to protect both organ and reduce the deleterious impact of the cardiovascular risk factor on the renal function considering both organs as a functional and physiopathological binomial.

The impact of renal function on efficacy and safety of new oral anticoagulant in atrial fibrillation patients: A systemic review and meta-analysis.

Background and objectivesThis meta-analysis was to investigate the efficacy and safety of new oral anticoagulant (NOAC) in atrial fibrillation (AF) patients with renal function insufficiency, and to explore whether renal decline occurs in AF patients with NOAC and its impact on outcomes.Methods and resultsIn AF patients with mild renal insufficiency, the NOAC was associated with significantly lower rates of stroke (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.67–0.91; P < .05). Lower rates of bleeding were significantly observed in NOAC group (OR, 0.85; 95% CI, 0.75–0.97; P < .05). In AF patients with moderate renal impairment, similar results were revealed (OR for stroke or systemic embolism, 0.80; 95% CI, 0.67–0.95, P < .05; OR for major bleeding, 0.78; 95% CI, 0.59–1.03; P = .07). During the follow-up, pooled data revealed that NOAC showed a less renal toxicity, but the difference did not reach statistical significance (creatinine clearance decline: −0.12 mL/min [−0.84, 0.61 mL/min]). We have revealed that the NOACs were associated with significantly lower rates of stroke or systemic embolism (hazard ratio [HR], 0.66; 95% CI, 0.42–0.89; P < .05) and lower rates of bleeding (HR, 0.93; 95% CI, 0.70–1.16; P = .153) in AF patients with worsening renal function.ConclusionsNOAC may have the potentiality to be at least as effective as warfarin and may equal safety outcomes in AF patients with renal impairment. Renal decline during therapeutics may be less likely happened in NOAC than warfarin dose. NOAC may reveal good efficacy and safety outcomes in these scenarios. Further detailed research is needed to gain more clear profile on this new anticoagulant.

Urotensin receptor antagonist palosuran attenuates cyclosporine-a-induced nephrotoxicity in rats.

Cyclosporine-A (CsA) is widely used for immunosuppressive therapy in renal transplantation. Nephrotoxicity is the main dose-limiting undesirable consequence of CsA. Urotensin II (U-II), a novel peptide with a powerful influence on vascular biology, has been added to the list of potential renal vascular regulators. Upregulation of the urotensin receptors and elevation of plasma U-II levels are thought to possibly play a role in the etiology of renal failure. The present study examines this hypothesis by evaluating renal function and histology with regard to the potential role of U-II and its antagonist, palosuran, in the pathogenesis of CsA-induced nephrotoxicity in rats. Male Sprague-Dawley rats were treated with CsA (15 mg/kg, for 21 days, intraperitoneally) or CsA + palosuran (300 mg/kg, for 21 days). Renal function was measured and histopathology, U-II immunostaining and protein detection with western blotting of the kidneys were performed. Cyclosporine-A administration caused a marked decline in creatinine clearance (Ccr). Fractional sodium excretion (FENa) tended to increase in the CsA-treated rats. Plasma U-II levels decreased in the CsA-treated rats. Cyclosporine-A treatment resulted in a marked deterioration in renal histology and an increase in the expression of U-II protein in the kidneys. Palosuran's improvement of renal function manifested as a significant decrease in serum creatinine levels and a significant increase in urine creatinine levels, resulting in a marked increase in Ccr. Palosuran produced a significant normalization of kidney histology and prevented an increase in U-II expression. Cyclosporine-A-induced renal impairment was accompanied by an increase in U-II expression in kidneys and a contrary decrease in systemic U-II levels. Palosuran improved the condition of rats suffering from renal dysfunction by preventing the decrease in renal U-II expression without affecting the systemic levels of U-II. The protective effect of palosuran in CsA nephrotoxicity is possibly independent of its U-II receptor antagonism.

SAT-179 RAS, SEH AND ETA BLOCKADE IN THE COURSE OF CHRONIC KIDNEY DISEASE IN 5/6 NEPHRECTOMIZED REN-2 TRANSGENIC RATS

Previous studies in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX) have shown that besides pharmacological blockade of the renin-angiotensin system (RAS) also increasing kidney tissue epoxyeicosatrienoic acids (EET) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for degradation of EETs, and endothelin type A (ETA) receptor blockade, retards chronic kidney disease (CKD) progression. Heterozygous TGR and age-matched Hannover-Sprague Dawley (HanSD) normotensive controls were used. Trandolapril and losartan were used as RAS blockade, cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB) as sEH blockade and atrasentan as ETA receptor blockade, administered in drinking water. 5/6 nephrectomy was done at the age of 6 weeks and 6 weeks later the appropriate treatment was started. Animals were treated with RAS blockade, a combination of RAS and sEH blockade, or a combination of RAS, sEH and ETA blockade. Survival rate, albuminuria, clearance of endogenous creatinine, glomerular damage (glomerulosclerosis index), and renal cortical tubulointerstitial injury were assessed. The addition of sEH inhibition to RAS blockade improved survival rate, further reduced albuminuria and renal glomerular and kidney tubulointerstitial injury, and attenuated the decline in creatinine clearance – all this as compared with 5/6 NX TGR treated with RAS blockade alone. Addition of ETA receptor antagonist to the combined RAS and sEH blockade not only offered no additional renoprotection but, surprisingly, abolished the beneficial effects of adding sEH inhibitor to the RAS blockade. These data indicate that pharmacological strategies that combine the blockade of RAS and sEH could be a novel tool to combat the progression of CKD. Any attempts to add additional substances to this therapeutic regime should be made with extreme caution.

Addition of Endothelin A-Receptor Blockade Spoils the Beneficial Effect of Combined Renin-Angiotensin and Soluble Epoxide Hydrolase Inhibition: Studies on the Course of Chronic Kidney Disease in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats

Introduction: Previous studies in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX) have shown that besides pharmacological blockade of the renin-angiotensin system (RAS) also increasing kidney tissue epoxyeicosatrienoic acids (EET) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for degradation of EETs, and endothelin type A (ET_A) receptor blockade retards chronic kidney disease (CKD) progression. This prompted us to evaluate if this progression will be alleviated by the addition of sEH inhibitor and ET_A receptor antagonist to the standard complex blockade of RAS (angiotensin-converting enzyme inhibitor plus angiotensin II type 1 receptor blocker) in rats with established CKD. Methods: The treatment regimens were initiated 6 weeks after 5/6 NX in TGR, and the follow-up period was 60 weeks. Results: The addition of sEH inhibition to RAS blockade improved survival rate, further reduced albuminuria and renal glomerular and kidney tubulointerstitial injury, and attenuated the decline in creatinine clearance – all this as compared with 5/6 NX TGR treated with RAS blockade alone. Addition of ET_A receptor antagonist to the combined RAS and sEH blockade not only offered no additional renoprotection but, surprisingly, also abolished the beneficial effects of adding sEH inhibitor to the RAS blockade. Conclusion: These data indicate that pharmacological strategies that combine the blockade of RAS and sEH could be a novel tool to combat the progression of CKD. Any attempts to further extend this therapeutic regimen should be made with extreme caution.

Renoprotective effects of the novel prostaglandin EP4 receptor-selective antagonist ASP7657 in 5/6 nephrectomized chronic kidney disease rats.

Prostaglandins (PGs) are important lipid mediators of numerous physiologic and pathophysiologic processes in the kidney. PGE2, the most abundant renal PG, plays a major role in renal physiology, including renin release and glomerular hemodynamics. We investigated the renoprotective properties of the novel PGE2 EP4 receptor-selective antagonist ASP7657 in 5/6 nephrectomized rats, a chronic kidney disease (CKD) model. Eight weeks of repeated administration of ASP7657 (0.001-0.1mg/kg) dose-dependently and significantly reduced urinary protein excretion and attenuated the development of glomerulosclerosis and tubulointerstitial damage, including fibrosis and inflammatory cell infiltration, without affecting blood pressure. Additionally, ASP7657 tended to have beneficial effects on renal function, as indicated by the decrease in plasma creatinine and blood urea nitrogen levels and attenuation of the decline in creatinine clearance (Ccr). The angiotensin II receptor blocker losartan (10mg/kg) also showed these renoprotective effects while significantly reducing blood pressure. ASP7657 dose-dependently and significantly reduced the EP4 receptor agonist-induced increase in plasma renin activity, as assessed by angiotensin I release in normal rats. Additionally, ASP7657 attenuated hyperfiltration assessed by Ccr without changing the renal blood flow or blood pressure in diabetic rats. These results suggest that ASP7657 suppresses the progression of chronic renal failure by modulating renin release and improving renal hemodynamics, and may therefore be a promising therapeutic option for inhibiting the progression of CKD.

Prognosis of geriatric patients with severe kidney disease.

Patients 75 years of age and older, with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (chronic kidney disease epidemiology CKD-EPI) were recruited. A comprehensive geriatric assessment was performed at hospital discharge. Comprehensive geriatric assessment was performed: Activities of daily livings and Instrumental activities of daily livings scores, of the risk of pressure sore with Exton-Smith scale, the cognitive status with MMSE score, nutritional status according to Mini-nutritional assessment short form and albuminemia, comorbidities with Cumulative illness rating scale, number of drugs in presciption and living status. Six months follow-up was performed to assess vital status and evolution of the eGFR. Sixty-seven patients were included, mean age 88.6±4.82 years with a mean eGFR of 21.3±6 mL/min. Mortality rate at six months was 36%. Multivariate analysis showed that a high CIRS score (RR=1.52; IC 95% 1.05-2.19) and a decline of creatinine clearance≥ 2 mL/min (4.72; 1.27-17.52) were predictive of mortality. On the opposite, a high MNA-SF score was protective (0.76; 0.62-0.94). Prognosis of geriatric patients with severe chronic kidney disease is poor. Comprehensive geriatric assessment helps to assess short-term prognosis, in a focus of person-centered care.

Potentially modifiable factors of dofetilide-associated risk of torsades de pointes among hospitalized patients with atrial fibrillation.

There is a significant variation in the clinical approach of initiation and dose adjustment of dofetilide in atrial fibrillation (AF). Excessive QT prolongation could predispose patients to torsades de pointes (TdP), which can be fatal. We performed a retrospective case-control study at Mayo Clinic Rochester (January 1, 2003 to December 31, 2016). "TdP risk" cases were defined as patients on dofetilide therapy for AF with subsequent TdP or excessive QTc prolongation requiring dose reduction or discontinuation (N = 31). A control group was matched 1:1 with cases by age, gender, year of admission, and dofetilide dose (N = 31). Using multivariate regression analysis, independent predictors of TdP risk included baseline QTc exceeding recommendations (adjusted odd ratio [AOR] 4.57; P = 0.023); underlying AF with rapid ventricular rate (AOR 16.95; P = 0.004); and diuretic therapy for acute heart failure (AOR 8.42; P = 0.007). Poor inter-observer agreement was identified among QT interval measurement in patients with AF and rapid ventricular rate compared to those in rate controlled AF or sinus rhythm. TdP risk cases receiving diuretics for acute heart failure had a significant decline in creatinine clearance than controls, although serum electrolytes and replacement did not differ among the two groups. Excessive QTc prolongation and AF with rapid ventricular rate at time of dofetilide initiation (likely due to difficulty in measuring QT intervals), and diuretic therapy for acute heart failure were independent factors for dofetilide-related TdP risk. Based on these data, possible preventive strategies could be adapted for safety protocols among hospitalized patients.

139 - Amlodipine and Calcineurin Inhibitor Induced Nephrotoxicity Following Allogeneic Hematopoietic Stem Cell Transplant

Background: Previous studies, primarily in the renal transplant population, have suggested that calcium channel blockers (CCBs) may protect against calcineurin inhibitor (CNI)-induced nephrotoxicity. However, this has not been evaluated in the hematopoietic stem cell transplant population. Methods: We reviewed data from 350 consecutive patients who underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) between 2006 and 2016 at a single institution to determine whether patients receiving amlodipine for hypertension had improved renal outcomes compared to patients who did not receive amlodipine. Subject data included up to one year from the initiation of a CNI. Results: Patients in the amlodipine group (n = 130) received 76 median days treatment with amlodipine and experienced a lesser median decline in creatinine clearance (CrCl) at predefined time points through day 180, as determined by a 2-tailed Mann-Whitney U-test. This trend remained through day 360 but did not reach statistical significance. At day 30, change in CrCl was -17.4 mL/min in the amlodipine cohort and -33.8 mL/min in the control group (P < .001). At day 180, median change in CrCl was -40.9 and -50.6 mL/min respectively (P = .005). A mixed-effects logistic regression model was used for multivariate analysis and found supra-therapeutic CNI levels (P < .0001), older age (P = .0006), past medical history of hypertension (P = .0171), and the use of antihypertensive medications other than amlodipine (P < .0001) correlated to a greater CrCl decline. For our secondary endpoint, we found that patients receiving amlodipine had a significantly lower risk of being hospitalized with acute kidney injury (AKI) (Figure 1). Probabilities of hospitalization were estimated utilizing the Kaplan-Meier method. Curves were compared and hazard-ratios calculated using log-rank tests. Hospitalization with AKI kidney injury occurred in 7.7% (10/130) of patients in the amlodipine cohort and 16.4% (36/220) of patients in the control group (P = .0218). Multivariate analysis found supratherapeutic CNI levels to also be an independent risk factor for hospitalization with AKI (P = .004). Patients receiving amlodipine were older (P = .005) and more likely to have a greater BMI (P = .0021), a greater baseline systolic and diastolic blood pressure (P < .0001), a lower baseline creatinine clearance (P = .016), and a past history of diabetes mellitus (P = .013) and hypertension (P < .0001) . Also, a higher rate of supratherapeutic CNI levels was found in the amlodipine cohort. Conclusion: Overall, we found more favorable renal outcomes in the amlodipine group despite holding greater baseline risks for renal decline compared to the control group. Our data support the use of amlodipine for hypertension in the allo-HSCT population and provide evidence suggesting that CCBs protect against CNI-induced nephrotoxicity.

Combined Inhibition of Soluble Epoxide Hydrolase and Renin-Angiotensin System Exhibits Superior Renoprotection to Renin-Angiotensin System Blockade in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats with Established Chronic Kidney Disease

Background/Aims: We found recently that increasing renal epoxyeicosatrienoic acids (EETs) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, shows renoprotective actions and retards the progression of chronic kidney disease (CKD) in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX). This prompted us to examine if additional protection is provided when sEH inhibitor is added to the standard renin-angiotensin system (RAS) blockade, specifically in rats with established CKD. Methods: For RAS blockade, an angiotensin-converting enzyme inhibitor along with an angiotensin II type receptor blocker was used. RAS blockade was compared to sEH inhibition added to the RAS blockade. Treatments were initiated 6 weeks after 5/6 NX in TGR and the follow-up period was 60 weeks. Results: Combined RAS and sEH blockade exhibited additional positive impact on the rat survival rate, further reduced albuminuria, further reduced glomerular and tubulointerstitial injury, and attenuated the decline in creatinine clearance when compared to 5/6 NX TGR subjected to RAS blockade alone. These additional beneficial actions were associated with normalization of the intrarenal EETs deficient and a further reduction of urinary angiotensinogen excretion. Conclusion: This study provides evidence that addition of pharmacological inhibition of sEH to RAS blockade in 5/6 NX TGR enhances renoprotection and retards progression of CKD, notably, when applied at an advanced stage.

The Regulatory T-cell Transcription Factor Foxp3 Protects against Crescentic Glomerulonephritis

Regulatory T cells (Tregs) have been shown to play a protective role in glomerulonephritis (GN) and Foxp3 is a master transcription factor in Treg development. In this study, we examined the functional role and mechanisms of Foxp3 in a mouse model of accelerated anti-glomerular basement membrane (anti-GBM) GN induced in antigen-primed Foxp3 transgenic (Tg) mice. Compared with littermate of wildtype (WT) mice in which induced severe crescentic GN developed with progressive renal dysfunction, Foxp3 Tg mice had reduced crescent formation, urinary protein excretion, plasma creatinine and decline in creatinine clearance. The protective role of Foxp3 in crescentic GN was associated with a markedly suppressed expression of proinflammatory interleukin-1 beta (IL-1β), tumour necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein 1 (MCP-1), and diminished infiltration of the kidneys by CD3+ T cells and F4/80+ macrophages. Moreover, overexpression of Foxp3 resulted in a significant increase in CD4+ Foxp3+ Tregs systemically and in the diseased kidneys, thereby blunting Th1, Th2, and Th17 responses systemically and in the kidneys. In conclusion, Foxp3 protects against kidney injury in crescentic GN through enhancement of Treg numbers and function, and suppression of Th1, Th2 and Th17 immune responses at the systemic and local tissue levels.