Reduction In Glomerular Filtration Rate Research Articles

On-Clamp vs. Off-Clamp Robot-Assisted Partial Nephrectomy for cT2 Renal Tumors: Retrospective Propensity-Score-Matched Multicenter Outcome Analysis.

Simple SummaryRobot-assisted partial nephrectomy is a viable option to treat tumors >7 cm. In this setting, however, the risk of postoperative renal function deterioration is higher because of the prolonged warm ischemia times (>20 min) that are required in two-thirds of cases, if an on-clamp approach is used. On the contrary, an off-clamp robotic partial nephrectomy is associated with shorter operation times and significantly improves the probabilities of achieving favorable perioperative outcomes.We compared perioperative outcomes after on-clamp versus off-clamp robot-assisted partial nephrectomy (RAPN) for >7 cm renal masses. A multicenter dataset was queried for patients who had undergone RAPN for a cT2cN0cM0 kidney tumor from July 2007 to February 2022. The Trifecta achievement (negative surgical margins, no severe complications, and ≤ 30% postoperative estimated glomerular filtration rate (eGFR) reduction) was considered a surrogate of surgical quality. Overall, 316 cases were included in the analysis, and 58% achieved the Trifecta. A propensity-score-matched analysis generated two cohorts of 89 patients homogeneous for age, ASA score, preoperative eGFR, and RENAL score (all p > 0.21). Compared to the on-clamp approach, OT was significantly shorter in the off-clamp group (80 vs. 190 min; p < 0.001), the incidence of sRFD was lower (22% vs. 40%; p = 0.01), and the Trifecta rate higher (66% vs. 46%; p = 0.01). In a crude analysis, >20 min of hilar clamping was associated with a significantly higher risk of sRFD (OR: 2.30; 95%CI: 1.13–4.64; p = 0.02) and with reduced probabilities of achieving the Trifecta (OR: 0.46; 95%CI: 0.27–0.79; p = 0.004). Purely off-clamp RAPN seems to be a safe and viable option to treat cT2 renal masses and may outperform the on-clamp approach regarding perioperative surgical outcomes.

Sex Differences In Glomerular Filtration Rate Reserve In Healthy Young Adults

PURPOSE: The prevalence of chronic kidney disease (CKD), defined as a sustained glomerular filtration rate (GFR) <60 mL/min/1.73m2, is higher in women compared to men. CKD can result from an insufficient number of functional nephrons necessary to maintain a healthy GFR. Functional nephron mass is lower in women compared to men, independent of differences in body size. Thus, women may be more susceptible to chronic reductions in GFR as a result of reductions in relatively fewer functional nephrons. Assessment of GFR reserve, which is defined as the ability to increase GFR in response to a protein load, is used to test the functional capacity of the kidneys to recruit nephrons. Whether GFR reserve differs between men and women is unknown. We tested the hypothesis that GFR reserve is lower in women vs. men. METHODS: Following 2 h of supine rest, healthy young men (n = 12) and women (n = 13, eumenorrheic, tested in the early follicular phase) ingested 1.2 g of whey protein per kg of body weight (fluid volume - men: 295 ± 48, women: 233 ± 27 mL, p < 0.001). Serum (sCr) and urinary (uCr) creatinine were measured pre-protein and 75- and 150-min post-protein ingestion to assess GFR via creatinine clearance (CrCl = uCr x urine flow rate ÷ sCr). Data are presented as mean ± SD RESULTS: Pre-protein, sCr was lower in women vs. men (0.9 ± 0.1 vs. 1.1 ± 0.1 mg/dL, p = 0.029), which was maintained post-protein (p ≤ 0.043). uCr was elevated above pre-protein levels (men: 35.7 ± 12.3, women: 21.8 ± 7.3 mg/dL) in both groups at 75- and 150- min post-protein (p ≤ 0.003), but uCr was higher in men at 150-min post-protein (104.1 ± 30.0 vs. 62.8 ± 24.7 mg/dL, p < 0.001). Urine flow rate decreased from pre- through post- protein (p < 0.001), and there were no differences between groups (p ≥ 0.723). CrCl increased from pre- to 150-min post- protein in men (122 ± 27 vs. 173 ± 89 mL/min, p = 0.002), but CrCl was not different from pre- (88 ± 18 mL/min) at any time post-protein in women (at 150-min post: 85 ± 32 mL/min, p ≥ 0.646), with CrCl at 150-min post-protein being higher in men (p < 0.001). The peak change in CrCl post-protein, independent of time, was greater in men vs. women (+57 ± 67 vs. 17 ± 20 mL/min, p = 0.052). CONCLUSIONS: The increase in CrCl following an oral protein load was lower in women compared to men, supporting that GFR reserve is lower in healthy young women vs. men.

Estimation of reduction of glomerular filtration rate in renal colic patients

Purpose: The aim of current study was to evaluate glomerular filtration rate (GFR) decline in patients with renal colic. Materials and methods: This descriptive analytical study was conducted on patients with definitive diagnosis of renal colic in university hospital of Sharjah. Data including gender, age, and underlying disease were extracted from medical records. GFR and creatinine level were assessed before and 3 months after stone excretion. Hydronephrosis severity was assessed by ultrasound procedure. Results: In current study, 224 patients with renal colic and mean age 45.6±11.35 years old were selected. The mean GFR before and 3 months after urinary stone excretion were 45.89±18.84 and 61.13±22.10 ml/minute, respectively (P&lt;0.01). The mean creatinine at the beginning and 3 months after urinary stone excretion was 1.93±0.46 and 1.59±0.43 mg/dl, respectively (P&lt;0.01). The most frequency of patients with different hydronephrosis degrees was related to score 3 (n=92). There was significant difference between hydronephrosis severity in terms of GFR (P=0.000). No significant difference was seen between the mean GFR at the beginning of the study and at 3 months after urinary stone excretion in terms of diabetes and hypertension (P&gt;0.05). Conclusion: We observed significant difference between hydronephrosis severity in terms of GFR.

A prospective study of living kidney donors: 6 years follow-up from a cardiovascular disease risk perspective.

SUMMARYOBJECTIVE:The purpose of this prospective study was to evaluate the clinical, laboratory, and donation-specific outcomes of living kidney donors 6 years after donation.METHODS:We included a total of 93 kidney donors and 54 age- and sex-matched individuals as control group through a type 2 cohort consecutive recruitment. We detected kidney function abnormalities and the presence of hypertension, diabetes, and cardiovascular events during the 6 years follow-up period.RESULTS:The mean serum creatinine levels were higher (p<0.001), and the estimated glomerular filtration rate levels were lower (p<0.001) in living kidney donors 6 years after donation when compared with controls. The protein/creatinine ratio of the study population was also higher (p=0.014). There was no difference in outcomes between the groups for end-stage kidney disease and cardiovascular mortality. A higher rate of new-onset hypertension (6.4 vs. 32.9%), diabetes mellitus (0.0 vs. 4.3%), chronic kidney disease (0.0 vs. 2.1%), and cardiovascular disease (0.0 vs. 2.1%) was demonstrated among donors 6 years after donation (p<0.001, respectively).CONCLUSION:Our data have demonstrated that the reduction in Glomerular filtration rate induced by kidney donation might cause an increase in adverse renal and cardiovascular events.

Non-diabetic urine glucose in idiopathic membranous nephropathy

This study aims to analyze the characteristics of idiopathic membranous nephropathy (iMN) with nondiabetic urine glucose during the follow-up. We retrospectively analyzed the data of 1313 patients who were diagnosed iMN. The prevalence of nondiabetic urine glucose during follow-up was 10.89%. There were significant differences between the patients with nondiabetic urine glucose and those without urine glucose in gender, hypertension ratio, proteinuria, N-acetyl-β-glucosaminidase, retinol binding protein, serum albumin, serum creatinine (Scr), cholesterol, triglyceride and positive anti-phospholipase A2 receptor antibody ratio, glomerular sclerosis ratio, acute and chronic tubular injury lesion at baseline. To exclude the influence of the baseline proteinuria and Scr, case control sampling of urine glucose negative patients was applied according to gender, baseline proteinuria and Scr. The proteinuria nonremission (NR) ratio was 45.83 versus 12.50% of the urine glucose positive group and case control group. Partial remission (PR) ratio of the two groups was 36.46 versus 23.96% and complete remission (CR) ratio was 19.79% versus 63.54%, respectively. Patients with urine glucose had higher risk of 50% estimated glomerular filtration rate (eGFR) reduction. Cox regression showed that urine glucose and baseline Scr were risk factors of 50% reduction of eGFR. Urine glucose remission ratio of the patients with proteinuria NR, PR, and CR was 13.33, 56.25, and 94.73% (p < 0.005). Patients who got urine glucose remission also had better renal survival. In conclusion, non-diabetic urine glucose was closely related to proteinuria. It could be applied as a tubular injury marker to predict renal function.

CKD-MBD biomarkers and CKD progression: an analysis by the joint model.

Biomarkers of chronic kidney disease-mineral and bone disorder (CKD-MBD) have been implicated in CKD progression in follow-up studies focusing on single measurements of individual biomarkers made at baseline only. The simultaneous relationship between the time trend of these biomarkers over the course of CKD and renal outcomes has never been tested. We applied the joint model (JM) to investigate the longitudinal relationship between repeated measurements of CKD-MBD biomarkers and a combined renal endpoint (estimated glomerular filtration rate reduction>30%, dialysis or transplantation) in 729 stage 2-5 CKD patients over a 36-month follow-up. In the survival submodel of the JM, the longitudinal series of parathyroid hormone (PTH) values was directly and independently related to the risk of renal events [hazard ratio (HR) (1 ln increase in parathyroid hormone (PTH) 2.0 (range 1.5-2.8), P<.001)] and this was also true for repeated measurements of serum phosphate [HR (1mg/dl) 1.3924 (range 1.1459-1.6918), P=.001], serum calcium [HR (1mg/dl) 0.7487 (range 0.5843-0.9593), P=.022], baseline fibroblast growth factor 23 [HR (1 pg/ml) 1.001 (range 1.00-1.002), P=.045] and 1,25-dihydroxyvitamin D [HR (1 pg/ml) 0.9796 (range 0.9652-0.9942), P=.006]. Repeated measurements of serum PTH, calcium and phosphate as well as baseline FGF23 and 1,25-dihydroxyvitamin D are independently related with the progression to kidney failure in a cohort of stage 2-5 CKD patients. This longitudinal study generates the hypothesis that interventions at multiple levels on MBD biomarkers can mitigate renal function loss in this population.

Regulation of Acid-Base Balance in Patients With Chronic Kidney Disease.

Normallly the kidneys handle the daily acid load arising from net endogenous acid production from the metabolism of ingested animal protein (acid) and vegetables (base). With chronic kidney disease, reduced acid excretion by the kidneys is primarily due to reduced ammonium excretion such that when acid excertion falls below acid porduction, acid accumulation occurs. With even mild reductions in glomerular filtration rate (60 to 90 ml/min), net acid excretion may fall below net acid production resulting in acid retention which may be initially sequestered in interstitial compartments in the kidneys, bones, and muscles resulting in no fall in measured systemic bicarbonate levels (eubicarbonatemic metabolic acidosis). With greater reductions in kidney function, the greater quantities of acid retained spillover systemically resulting in low pH (overt metabolic acidosis). The evaluation of acid-base balance in patients with CKD is complicated by the heterogeneity of clinical acid-base disorders and by the eubicarbonatemic nature of the early phase of acid retention. If supported by more extensive studies, blood gas analyses to confirm the acid-base disorder and newer ways for assessing the presence of acidosis such as urinary citrate measurements may become routine tools to evaluate and treat acid-base disorders in individuals with CKD.

Hemostasis and oxidative stress in chronic kidney disease in children and adolescents.

Chronic kidney disease (CKD) can be defined as the progressive loss of renal function, characterized by a decreased glomerular filtration rate (GFR). The etiology of CKD in childhood is mainly associated with congenital anomalies of the kidneys and urinary tract (CAKUT) and with glomerular diseases. The goal of this study was to investigate the hemostasis and oxidative stress in pediatric CKD of different etiologies. Fifty-four CKD children and adolescents and 52 controls were enrolled in this study. The evaluation of hemostasis was carried out by determination of D-dimer (D-Di) and plasminogen activator inhibitor (PAI-1) plasma levels, while oxidative stress was evaluated by thiobarbituric acid reactive substance (TBARS) levels, protein carbonyl content, plasma antioxidant capacity (MTT), and ascorbate. The D-Di was increased in CAKUT stage 3 or 4 patients compared with those with glomerular disease. PAI-1 was increased in patients with glomerular disease compared with CAKUT. Carbonyl protein content was higher in the control group compared with glomerular disease stage 3 or 4 patients. Our findings showed that the reduction in GFR is associated with a state of hypercoagulability. The analysis of integrated networks showed an expansion of connections among hemostatic and oxidative stress markers in CKD children and adolescents compared with controls.

Risk factors for renal impairment in patients with hematological cancer receiving antineoplastic treatment.

Antineoplastic treatments, mainly chemotherapy, affect the kidneys, causing toxicity, and can trigger acute and chronic kidney injuries. This study aimed to analyze the prevalence of renal disorders in patients with oncohematological neoplasms receiving antineoplastic treatment. This retrospective cohort study included 75 patients with hematological cancer who underwent chemotherapy between 2012 and 2018 in the Hematology Sector of the Walter Cantídeo University Hospital of the Federal University of Ceará. Sociodemographic and clinical data, blood biochemical assessment findings, and glomerular filtration rate (GFR) were analyzed using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The data were tabulated; transferred to the Statistical Package for the Social Sciences software, version 20.0; and analyzed using Pearson's chi-square test or Fisher's exact test for categorical variables followed by a multinomial logistic regression model (p < 0.05). The prevalence of renal disorders was 52.4% according to the CKD-EPI equation for GFR events. There was a significant association between the decrease in GFRs and the following variables: female sex (p = 0.002), diagnosis of multiple myeloma (p = 0.008), start of treatment within 40days (p = 0.005), and the following antineoplastic treatments: cyclophosphamide, vincristine, and prednisone (p = 0.026); irarubicin (p = 0.032); azacytidine, dexamethasone, and cyclophosphamide (p < 0.001); zoledronic acid (p < 0.001); and pamidronate (p = 0.012). CALGB 8811 (p < 0.001) was inversely associated with a reduction in the GFR. The prevalence of renal disorders was high in patients with oncohematological neoplasms receiving antineoplastic treatment. This requires periodic monitoring of the evaluation of renal function since reductions in GFRs were significantly associated with different treatment protocols used.

Usefulness of urinary biomarkers to estimate the interstitial fibrosis surface in diabetic nephropathy with normal kidney function.

Kidney biopsies of patients with diabetic nephropathy (DN) and normal kidney function may exhibit interstitial fibrosis (IF) without reduction of glomerular filtration rate (GFR) because of hyperfiltration. The aim of our study was to analyse the performance of a set of biomarkers of tubular injury to estimate the extent of IF in patients with DN and normal kidney function. This cross-sectional study included 118 adults with DN diagnosed by kidney biopsy and GFR≥90mL/min/1.73 m2 and a control group of healthy subjects. We measured the urinary excretion of monocyte chemoattractant protein-1 (MCP-1) neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), β2-microglobulin and dickkopf-3 protein (DKK-3) at the time of kidney biopsy. GFR was measured by chromium-51 labeled ethylenediamine tetraacetic acid (Cr-EDTA) (measured GFR). IF was quantified using a quantitative morphometric procedure. Predictive multivariate models were developed to estimate the IF surface. Patients with DN showed significantly higher levels of DKK-3, MCP-1 and L-FABP and significantly lower levels of epidermal growth factor (EGF) than healthy controls. There were no significant between-group differences in the levels of β2-microglobulin, KIM-1 or NGAL. IF was negatively associated with EGF and positively with age, proteinuria, MCP-1, DKK-3 and L-FABP, but not with β2-microglobulin, KIM-1, NGAL or GFR. The best model to predict IF surface accounted for 59% of its variability and included age, proteinuria, EGF, DKK-3 and MCP-1. Our study provides a model to estimate the IF in DN that can be useful to assess the progression of IF in patients with normal kidney function.

Galectin-3 as a Marker of Cardiorenal Syndrome in Patients with Chronic Heart Failure

Aim. To assess the effect of renal dysfunction on the galectin-3 level in patients with chronic heart failure (HF) with preserved, intermediate and reduced left ventricular ejection fraction (EF).Material and methods. Along with a clinical examination, 69 patients with HF (NYHA class II-IV) underwent tests for the level of NT-proBNP and galectin-3 in serum using enzyme immunoassay.Results. Study participants were divided into 3 groups: 23 patients with preserved EF (HFpEF), 26 patients with midrange EF (HFmrEF), 20 patients with reduced EF (HFrEF). There was a trend to increase the concentration of galectin-3 with increase in NT-proBNP level. Correlation analysis showed significant feedback (r=−0.41, p&lt;0.05) between galectin-3 and EF only in patients with preserved systolic function. In the same group of HFpEF patients, the maximum serum galectin-3 level was 10.5 [6.5; 14.5] ng/ml. Serum galectin-3 level showed negative correlated with the GFR in patients with CHF (r=−0.513, p&lt;0.05). In patients with HF and glomerular filtration rate (GFR) &lt;60 ml/min/1.73 m2 it was higher than in patients with GFR&gt;60 ml/min/1.72 m2 (9 [5.3; 12.6] ng/mL vs 11.8 [6.2; 15.3] ng/mL, p&lt;0.05). According to the ROC-analysis data, galectin-3 level &gt;10.3 ng/ml indicates a high risk of chronic kidney disease stage 3-4 stage development (sensitivity 60%, specificity 75%) and can be considered as a risk factor for development of cardiorenal syndrome in HF patients.Conclusion. Galectin-3 level in patients with HF is more influenced by the degree of reduction in GFR rather than the left ventricular systolic function impairment.

MO617: Liraglutide Improves Both Diabetic Nephropathy and Cardiomyopathy in the SDT Fatty Rat, A Cardiorenal Model of Type 2 Diabetes

Abstract BACKGROUND AND AIMS The Glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide (LIRA) has cardioprotective effects and may reduce the development of kidney disease in type 2 diabetic patients. We here evaluated the effects of LIRA on both kidney and heart function in the Spontaneously Diabetic Torii (SDT) fatty rat, a type 2 diabetic cardiorenal model. METHOD SDT fatty male rats were treated subcutaneously with vehicle or LIRA 0.4 mg/kg QD for 10 weeks. To measure the effects of LIRA on glomerular hyperfiltration, rats were injected with FITC-sinistrin to measure glomerular filtration rate (GFR) at 4 weeks of treatment. At 5 weeks of treatment, rats underwent unilateral nephrectomy and were put on a 0.3% salt diet to induce a GFR decline. GFR was then measured at 10 weeks of treatment, before hemodynamics measurement and echocardiography. RESULTS Compared with vehicle, LIRA induced significant body weight loss, as well as blood glucose levels reduction by up to ∼20%. During the hyperfiltration phase, LIRA attenuated hyperfiltration, with a 19% lower GFR versus vehicle (P &amp;lt; 0.05). In vehicle-treated animals, unilateral nephrectomy and 0.3% salt diet induced a major reduction (−56%) in GFR, as expected. After 10 weeks of treatment, LIRA markedly attenuated this GFR decline (vehicle: 9.3 ± 0.5 mL/min/kg; LIRA: 13.3 ± 0.9 mL/min/kg, P &amp;lt; 0.001 versus vehicle). Compared with vehicle, LIRA also lowered urine albumin-to-creatinine ratio both in the hyperfiltration and GFR decline phases, and significantly reduced kidney inflammation and fibrosis histology scores. LIRA showed significant reduction in cardiac hypertrophy, as well as both arterial and left ventricle end-systolic pressures. Moreover, LIRA normalized the diastolic dysfunction with preserved ejection fraction observed in SDT fatty rats (P &amp;lt; 0.001 versus vehicle). CONCLUSION In the SDT fatty rat, LIRA shows significant benefits by reducing renal hyperfiltration, preventing GFR decline, and improving cardiac hypertrophy, blood pressure and diastolic dysfunction. This preclinical model will be useful to evaluate drugs targeting the cardiorenal axis in type 2 diabetes.

MO431: Estimation of the Risk of Progression and Renal Substitution Treatment in Patients With Chronic Kidney Disease Using an Artificial Intelligence Model

Abstract BACKGROUND AND AIMS The use of tools that allow to estimate the probability of progression of chronic kidney disease (CKD) to advanced stages, has not yet gained a notable space in our clinical practice. The aim of this study was to develop and validate a model to predict disease progression, and the need for renal replacement therapy, based on machine learning, for patients with CKD grades 3 to 5. This is the first model of its kind to be implemented in Colombia. METHOD This is an observational retrospective closed cohort study. We included patients with CKD from a primary care program and followed them for 5 years. Demographic, clinical and laboratory predictors were included. The outcomes were CKD stage progression, &amp;gt;25% reduction in baseline glomerular filtration rate (eGFR) and the need for renal replacement therapy (RRT), dialysis, or kidney transplantation. We designed two prediction models, one time-independent, based on logistic regression, neural networks and random forest; and a second model, a survival analysis (time to event), by Cox regression, random forest and gradient boosting. Finally, we conducted an internal validation with bootstrapping for the first model, and external validation for the second model in a second real cohort. As a result, we designed a risk calculator. RESULTS Time-independent model included 2619 patients, 62.7% female, 92.6% with hypertension, 23.5% diabetics, with a baseline eGFR 51.06 mL/min/1.73m2 (40–61.9). An estimated performance for predicting RRT risk of F1: 0.61 and Kappa: 0.60 (113 events) was detected; stage progression of F1: 0.4 and Kappa: 0.25; reduction in eGFR F1: 0.29 and Kappa: 0.21. For this first model, the most relevant predictors were: initial eGFR, hemoglobin, sex, central region, total cholesterol and socioeconomic status. The second, a 5-year Time-to-Event prediction model, included data from 1803 patients, had good accuracy with a C-Index assessed performance for RRT risk of 0.96, grade progression of 0.71 and eGFR reduction of 0.69 respectively. The most relevant predictors were initial eGFR, mean heart rate, hemoglobin, hospitalizations, sex, hypertension, diabetes, total cholesterol and central region. The validation cohort, with 658 patients with CKD, 63.9% male, 39% diabetics, with a mean eGFR of 34.9 mL/min/1.73m2, showed good accuracy with a C-Index for RRT risk of 0.935, grade progression of 0.69 and eGFR reduction of 0.0.62 respectively. CONCLUSION Our study demonstrated the utility of novel tools to predict renal outcomes in a CKD population in Colombia. This is the first study conducted with our local population. The resulted risk calculator is intended to be part of the electronic medical history in our hospitals.

MO271: A Single Dose of Lithium Protects Against Renal Injury Following Bilateral Ureteral Obstruction

Abstract BACKGROUND AND AIMS Obstructive nephropathy decreases renal blood flow (RBF) and glomerular filtration rate (GFR). Glycogen synthase kinase 3β (GSK3 β), an apoptotic enzyme, is increased in a model of unilateral obstruction. Treatment with a single dose of lithium, a selective inhibitor of GSK3β, accelerated recovery of renal function in models of cisplatin and ischemia-reperfusion induced acute kidney injury (AKI). The aim of this study was to evaluate the efficacy of a single dose of lithium in the treatment of AKI induced by bilateral ureteral obstruction (BUO) METHOD Adult male Wistar rats were divided in four groups: (i) sham (sham operated); (ii) lithium: rats treated with lithium chloride 80 mg/Kg BW Intraperitonially (IP); (iii) BUO during 24 h; (iv) BUO during 24 h and treated with the same dose immediately after ureteral desobstruction. The rats were anesthetized 48 h after desobstruction to measure inulin clearance and renal blood flow. At the end of the clearance experiments, the rats were euthanized and the kidneys were removed to measure GSK3 β renal expression. RESULTS As described in the Table 1, BUO showed markedly reduction of GFR and RBF associated with an increase of GSK3β. A single dose of lithium administration ameliorated all these alterations. CONCLUSION Lithium treatment attenuated renal dysfunction in this model of BUO-associated AKI by improving inulin clearance. These therapeutic effects were due to an inhibition of renal expression of GSK3β. This may be a new therapeutic approach for BUO-induced AKI.

Impact of eGFR rate on 1-year all-cause mortality in patients with stable coronary artery disease

BackgroundCoronary artery disease (CAD) is a leading cause of mortality and is often complicated by chronic kidney disease. We sought to investigate the prevalence of different degree of estimated glomerular filtration rate (eGFR) reduction, the clinical and bio-humoral correlates, its relationship with therapeutic management, and its predictive role on 1-year all-cause mortality, in patients with stable CAD. MethodsWe studied 4,130 patients with stable CAD recruited in a prospective, observational, nationwide study (START, STable coronary Artery diseases RegisTry) in Italy. Baseline clinical characteristics, pharmacological treatment, and all-cause 1-year mortality were evaluated according to groups of eGFR (<30; 30-59; 60-89; ≥90 ml/min/1.73 m2) at baseline. ResultsThe presence and the degree of chronic kidney disease entailed an unfavorable risk profile, since it was gradually associated with more comorbidities. Furthermore, progressively lower eGFR values were associated to lower diastolic blood pressure and hemoglobin values. As eGFR lowers, optimal medical treatment and its persistence overtime is reduced. Multivariate analysis showed that progressively lower eGFR significantly correlated with all-cause 1-year mortality [hazard ratio (HR): 1.02; 95% confidence intervals (CI): 1.01-1-03; p = 0.0001]. ConclusionsLow eGFR is associated with an increasing risk of all-cause mortality in patients with stable CAD. Chronic kidney disease may hamper the optimization of treatment limiting the use of drugs which may favorably impact cardiovascular and renal outcomes.

Glomerular Filtration Rate Reserve During Mild Passive Heat Stress Does Not Differ Between Younger Men and Women

PurposeThe incidence of acute kidney injury during heat waves is higher in young women compared to young men. Acute kidney injury is clinically defined as an abrupt reduction in glomerular filtration rate (GFR). The magnitude of reduction in GFR during acute kidney injury is reflective of the availability of functional nephrons. Functional nephron mass is lower in women compared to men. Therefore, women may be at a greater risk of AKI during heat waves due to a reduced ability to maintain GFR. In a heterogenous group of men and women, we have recently demonstrated that GFR reserve, which is defined as the capacity to increase GFR in response to an increase in functional demand (e.g., oral protein load), is reduced with passive heat stress. This study tested the hypothesis that GFR reserve is lower in women compared to men during passive heat stress.MethodsFollowing 2 hours of passive heat stress (water perfused suit), healthy young men (n=13) and women (n=12, eumenorrheic, tested in the early follicular phase) ingested a whey protein shake (1.2 g of protein/kg of body weight) to test GFR reserve. Serum (sCr) and urinary (uCr) creatinine and urine flow rate were measured pre‐protein, and 75‐min and 150‐min post‐protein ingestion. GFR was estimated from creatinine clearance (CrCl = uCr x urine flow rate ÷ sCr). Data are presented as mean ± SD.ResultsThe increase in core temperature pre‐protein (men: 0.7 ± 0.2, women: 0.8 ± 0.2°C, p=0.829) and total body fluid loss (men: ‐2.9 ± 0.7, women: ‐2.9 ± 0.8%, p=0.926) did not differ between men and women. sCr did not differ between men (pre‐protein: 1.1 ± 0.2 mg/dL) and women (pre‐protein 1.0 ± 0.1 mg/dL) at any time (p=0.097) and did not change from pre‐ following protein ingestion (p=0.107). uCr was elevated above pre‐protein levels (men: 94.4 ± 78.4, women: 40.0 ± 14.0 mg/dL) in both men and women at 75‐ and 150‐ min post‐protein (p≤0.011) but did not differ between groups at any time (p≥0.105). Urine flow rate was reduced post‐protein (p&lt;0.001), but there were no differences between men and women (p=0.331). Pre‐protein CrCl was higher in men (130 ± 32 mL/min) versus women (89 ± 12 mL/min, p=0.005), which was maintained throughout the post‐protein period (p≤0.005). CrCl increased by 15 ± 19 mL/min from pre‐ to 150‐min post‐protein in men (p=0.022) but did not differ from pre‐protein in women (change at 150‐min post‐protein: +9 ± 21 mL/min, p=0.568). However, the peak increase in CrCl post‐protein, independent of time, did not differ between men (+19 ± 19 mL/min) and women (+11 ± 19 mL/min, p=0.193).ConclusionDuring mild passive heat stress, the magnitude of increase in CrCl following an oral protein load did not differ between young healthy men and eumenorrheic women tested in the early follicular phase of the menstrual cycle. Thus, biological sex differences in GFR reserve during heat exposure do not likely contribute to the increased risk of acute kidney injury during heat waves in young women when estrogen is at its lowest levels. Whether GFR reserve during passive heat stress is modified by the menstrual cycle phase requires further investigation.

Role of Proximal Tubule DPP4 in Inflammation and Kidney Disease Progression

Obesity and overweight leads to an entity called obesity related kidney disease (ORKD), which is a major risk factor for chronic kidney disease (CKD) progression to End Stage Renal Disease and/or dialysis. ORKD is characterized by proximal tubule brush border vacuolization and injury, basement membrane thickening, glomerular accumulation of fat globules and glomerulomegaly. We have developed a mouse model of Western diet (high fat and high sucrose)‐induced obesity that manifests all the features of ORKD. In addition, our lab observed that obese mice fed a Western diet, manifest early hyperfiltration (3 months into feeding). It is later followed by reduction in glomerular filtration rate (GFR, beginning at 18 months of age), and this pattern mimics human diabetic kidney disease progression. Our lab also observed that in ORKD, there is increased Dipeptidyl Peptidase 4 (DPP4) activity in the kidney, especially the proximal tubules and proximal tubule specific deletion of DPP4 improves the GFR. Lastly, our lab demonstrated that there is a major role for inflammation in the obese kidney and DPP4 inhibitors mitigate the inflammation. However, it is not known if and how proximal tubule DPP4 contributes to inflammation and pathophysiological changes in ORKD. Therefore, we hypothesized that proximal tubule DPP4 mediates inflammation and contributes to the pathophysiological changes in ORKD, thereby identifying DPP4 as a target to prevent CKD progression.MethodsProximal tubule specific DPP4fl/fl;SGLT2Cre+ (PT DPP4KO) and DPP4fl/fl;SGLT2Cre‐ (PT DPP4WT) mice were fed a WD and control chow (CD) for 6 mths, 15 mths and till sacrifice (18 to 27 mths). Inflammation was assessed both by flow cytometry assessment of kidney immune cells and expression of pro and anti‐inflammatory genes and proteins).ResultsThere were more pro‐inflammatory as well as DPP4 expressing macrophages in the WD‐fed WT group compared to the KO group (p&lt;0.05). There was also activation of the T‐cells in particular the CD8s which was suppressed in the KO group (p&lt;0.05). Deep sequencing of kidney mRNA revealed activation of pro‐inflammatory cytokines including Th1, Th17, M1 macrophage‐based cytokines and TLR4 and ICAM‐1. The KO group showed improvement in both TLR4 and ICAM‐1 (p&lt;0.05). At the protein level, there was an increase in pro‐fibrotic (Desmin) and pro‐inflammatory (ERK) proteins in the WD‐fed WT groups and phosphorylation of ERK was suppressed in the KO group (p&lt;0.05). When inflammation was assessed across the months it seemed that the earliest changes were in the growth pathways and beta‐oxidation of lipids, followed by the more inflammatory genes later in the course of the disease.ConclusionWD feeding led to hyperfiltration followed by a decline in GFR that was partly mitigated by PT deletion of DPP4 and this was associated with improved kidney histology and less fibrosis. WD feeding in WT mice was associated with increase in expression of several pro inflammatory genes and TLR4 and ICAM 1 were normalized in KO mice. DPP4 protein expression in kidney was associated with increased phosphorylation of ERK and this was suppressed in KO mice. Overall, these data suggest that suppression of early activation of DPP4 in ORKD may slow down the progression of CKD.

Short-Term Mortality in Patients with Heart Failure at the End-of-Life Stages: Hades Study.

Background: Information regarding short-term vital prognosis in patients with heart failure at advanced stages of the disease is scarce. Objective: To develop a three-month mortality predictive model for patients with advanced heart failure. Methods: Prospective observational study carried out in primary care and a convalescence community facility. Heart failure patients either New York Heart Association (NYHA) III with at least two HF hospitalizations during the previous six months or NYHA IV with/without previous recent hospitalization were included in the study. Multivariable predictive models using Cox regression were performed. Results: Of 271 patients included, 55 (20.3%) died during the first three months of follow-up. Mean age was 84.2 years (SD 8.3) and 59.8% were women. Predictive model including NT-proBNP had a C-index of 0.78 (95% CI 0.71; 0.85) and identified male gender, low body mass index, high potassium and NT-proBNP levels, and moderate-to-severe dependence for daily living activities (Barthel index < 40) as risk factors of mortality. In the model without NT-proBNP, C index was 0.72 (95% CI 0.64; 0.79) and, in addition to gender, body mass index, low Barthel index, and severe reductions in glomerular filtration rate showed the highest predictive hazard ratios for short-term mortality. Conclusions: In addition to age, male gender, potassium levels, low body mass index, and low glomerular filtration, dependence for activities of daily living add strong power to predict mortality at three months in patients with advanced heart failure.

Multisystem Inflammatory Syndrome in Children and Acute Kidney Injury: Retrospective Study of Five Italian PICUs.

Multisystem inflammatory syndrome in children (MIS-C) manifests with heart dysfunction and respiratory failure some weeks after a severe acute respiratory syndrome coronavirus disease 2 infection. The aim of our study was to explore the prevalence, severity, timing, and duration of acute kidney injury (AKI) in MIS-C patients. Furthermore, we evaluated which clinical variables and outcomes are associated with AKI. Multicenter retrospective study. Five tertiary hospital PICUs in Italy. Data were collected in the first 7 days of PICU admission and renal function was followed throughout the hospital stay. Patients less than 18 years old admitted to the PICU for greater than 24 hours with MIS-C. None. We collected the following data, including: demographic information, inflammatory biomarkers, lactate levels, Pa o2 /F io2 , ejection fraction, N-terminal pro-B-type natriuretic peptide (NT-proBNP), renal function (serum creatinine, urinary output, fluid balance, and percentage fluid accumulation), Vasoactive-Inotropic Score (VIS), pediatric Sequential Organ Failure Assessment (pSOFA), and Pediatric Index of Mortality 3. AKI was diagnosed in eight of 38 patients (21%) and severe AKI was present in four of eight patients. In all cases, AKI was present at PICU admission and its median (interquartile range) duration was 3.5 days (1.5-5.7 d). We did not identify differences between AKI and no-AKI patients when not making correction for multiple comparisons, for example, in weight, ejection fraction, pSOFA, Pa o2 /F io2 , and lactates. We failed to identify any difference in these groups in urine output and fluid balance. Exploratory analyses of serial data between no-AKI and AKI patients showed significant differences on lymphocyte count, NT-proBNP value, ejection fraction, pSOFA, Pa o2 /F io2 , and VIS. In this multicenter Italian PICU experience, MIS-C is associated with AKI in one-in-five cases. In general, AKI is characterized by an associated reduction in glomerular filtration rate with a self-limiting time course.

The Treatment of Heart Failure in Patients with Chronic Kidney Disease: Doubts and New Developments from the Last ESC Guidelines.

Patients with heart failure (HF) and associated chronic kidney disease (CKD) are a population less represented in clinical trials; additionally, subjects with more severe estimated glomerular filtration rate reduction are often excluded from large studies. In this setting, most of the data come from post hoc analyses and retrospective studies. Accordingly, in patients with advanced CKD, there are no specific studies evaluating the long-term effects of the traditional drugs commonly administered in HF. Current concerns may affect the practical approach to the traditional treatment, and in this setting, physicians are often reluctant to administer and titrate some agents acting on the renin angiotensin aldosterone system and the sympathetic activity. Therefore, the extensive application in different HF subtypes with wide associated conditions and different renal dysfunction etiologies remains a subject of debate. The role of novel drugs, such as angiotensin receptor blocker neprilysin inhibitors and sodium glucose linked transporters 2 inhibitors seems to offer a new perspective in patients with CKD. Due to its protective vascular and hormonal actions, the use of these agents may be safely extended to patients with renal dysfunction in the long term. In this review, we discussed the largest trials reporting data on subjects with HF and associated CKD, while suggesting a practical stepwise algorithm to avoid renal and cardiac complications.