Kidney Function Decline In Patients Research Articles

Novel Urinary Biomarkers and Chronic Kidney Disease After Coronary Angiography: A Prospective Case-Controlled Study

BACKGROUND: Novel urinary biomarkers may have potential for early detection of acute kidney injury.
 AIM: The aim of the study was to test two urinary biomarkers: Kidney injury molecule-1(KIM-1) and liver-type fatty acid binding protein (L-FABP) as markers of kidney injury following coronary angiography.
 METHODS: This is a prospective non-randomized controlled trial, performed in two large teaching hospitals. Patients were recruited from the catheter lab or form nephrology outpatient clinics. In group (A), 100 patients with AKI on top of CKD after coronary angiography and Group B: Thirty-one patients with stable CKD as a control. KIM-1 and L-FABP were measured at base line and after 3 months. 
 RESULTS: In group (A), 100 patients who had acute on top of CKD after coronary angiography, stage progression occurred in 15 patients in group (A) compared to two patients in group (B) (p = 0.28). The median change in eGFR after 3 months was not statistically significant between both groups (p = 0.8). Median baseline urinary liver-type fatty acid binding protein was higher in Group A compared to Group B (3.7 μg/g vs. 1.82μg/g). The change in L-FABP from baseline to 3 months was significant between both groups (p < 0.001). The median urinary concentrations of KIM-1 and L-FABP were higher at the end of the follow-up compared to base line values in both groups, (p < 0.000).
 CONCLUSION: Urinary L-FABP correlates with kidney function decline in patients with acute on top of CKD after coronary angiography. Urinary levels of KIM-1 and L-FABP at 3 months increase significantly compared to baseline in patients with progressive CKD.

Tolvaptan or transplant: why wait?

The vasopressin V2-receptor antagonist tolvaptan has been approved in multiple countries to slow kidney function decline in patients at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). The efficacy, side effects, and risks associated with tolvaptan are described in detail in the accompanying article.2 A question that has arisen in our clinical practice is whether the potential benefit of tolvaptan in delaying the progression of ADPKD outweighs the daily impact of increased aquaresis and the risk of hepatotoxicity.

Ambulatory blood pressure variability and risk of cardiovascular events, all-cause mortality, and progression of kidney disease.

Association between blood pressure (BP) variability and cardiovascular outcome remains unclear in patients with chronic kidney disease (CKD). We evaluated this association between ambulatory BP variability and cardiovascular events, mortality, and kidney disease progression in patients with CKD. From the Cardiovascular and Metabolic Disease Etiology Research Center-HIgh Risk study (2013-2018), a total of 470 patients with CKD were analyzed. Ambulatory BP variability was assessed using average real variability (ARV). Primary outcome was composite of nonfatal myocardial infarction, nonfatal stroke, and all-cause mortality. The secondary outcome was rapid kidney function decline [estimated glomerular filtration rate (eGFR), >3 ml/min per 1.73m per year]. During a median follow-up of 51.8 (40.5-56.2) months, the incidences of all-cause death and composite outcomes were higher in the high SBP-ARV group than in the low SBP-ARV group. The Kaplan-Meier analysis showed that a high SBP-ARV, but not a high DBP-ARV and heart rate-ARV, was associated with higher composite outcome risks. In multivariable Cox analysis, a high SBP-ARV correlated with increased composite outcome risks (hazard ratio, 4.53; 95% confidence interval, 1.41-14.58). When subgroup analysis was performed (low vs. high 24-h SBP), this association was only significant in the high 24-h SBP group. The risk stratification for composite outcomes by adding SBP-ARV into the basic model and 24-h SBP, improved by 1.3%. Furthermore, the mean eGFR decline rate was faster, and the rapid eGFR decline risk was 1.68-fold higher in the high SBP-ARV group. Greater ambulatory SBP variabilities were associated with increased risks for nonfatal cardiovascular diseases, all-cause mortality, and rapid kidney function decline in patients with CKD.

499-P: Clinical Validation of an AI-Enabled Prognostic Test (KidneyintelX) to Accurately Predict Rapid Kidney Function Decline in Patients with Type 2 Diabetic Kidney Disease

The ability to predict rapid kidney function decline (RKFD) in patients with early stages of type 2 diabetic kidney disease (T2DKD) can improve long-term health outcomes through earlier intervention. Our objective was to develop a robust risk score for patients with early stages of T2DKD. We obtained EHR and plasma from patients with T2DKD (Kidney Disease Improving Global Outcomes [KDIGO] G1-G2, A2-A3 or G3a-G3b, A1-A3) from the Mount Sinai BioMe Biobank and the Penn Medicine Biobank and measured soluble tumor necrosis factor receptor (sTNFR1, sTNFR2) and kidney injury molecule-1 (KIM-1) via a validated quantitative electrochemiluminescent assay. A machine learning model was trained using the EHR/biomarker data to predict RKFD, defined as eGFR decline of ≥5 ml/min/year or ≥40% sustained decline in eGFR or kidney failure within 5 years, and performance was compared to a clinical model and KDIGO risk-matrix. A total of 1146 subjects with a mean age of 63, baseline eGFR 54 ml/min, and median UACR 61 mg/g were randomly divided into 60% training (n=686) and 40% validation (n=460) sets. The median follow-up was 4.3 years and 241 (21%) experienced RKFD. The AUC of KidneyIntelX for RFKD was 0.85 (95% CI 0.84-0.86) in training and 0.77 (95% CI 0.76-0.79) in the validation set vs. AUC of 0.67 (95% CI 0.64-0.70) for a clinical model. Using pre-specified cutoffs from the training set, KidneyIntelX stratified 47%, 37% and 16% of the validation set into low-, intermediate- and high-risk strata, with a PPV of 62% (vs. 41% for KDIGO) in the high-risk group (p <0.001), a net reclassification improvement for events of 41% (p <0.05), and a NPV of 91% in the low-risk group (vs. 85% for KDIGO). KidneyIntelX, a machine learning model combining biomarkers and EHR data, improved prediction of RKFD over standard clinical metrics in patients with T2DKD. Future studies will prospectively evaluate KidneyIntelX in clinical decision-making and impact. Disclosure L. Chan: None. G.N. Nadkarni: Advisory Panel; Self; Renalytix AI. Consultant; Self; AstraZeneca, Reata, Renalytix AI. Stock/Shareholder; Self; Renalytix AI. Other Relationship; Self; Renalytix AI. F. Fleming: Board Member; Self; Renalytix AI plc. F.E. Salem: None. B. Murphy: Board Member; Self; RenalytixAI. M.J. Donovan: Consultant; Self; Renalytix AI plc. S. Coca: Advisory Panel; Self; Renalytix AI plc. Consultant; Self; Bayer Healthcare Pharmaceuticals Inc., CHF Solutions, Relypsa, Inc., Takeda Pharmaceutical Company Limited. Stock/Shareholder; Self; Renalytix AI plc. S.M. Damrauer: Consultant; Spouse/Partner; Rhythm Pharmaceuticals. Research Support; Self; CytoVas LLC, Renalytix AI plc. Funding Renalytix AI plc

P1625HIGHER DIETARY ACID LOAD IS ASSOCIATED WITH INCREASED RISK FOR KIDNEY FUNCTION DECLINE AND GRAFT FAILURE IN KIDNEY TRANSPLANT RECIPIENTS

Abstract Background and Aims Dietary acid load is associated with low grade metabolic acidosis and might accelerate kidney function decline in patients with chronic kidney disease (CKD). We investigated whether dietary acid load, estimated as net endogenous acid production (NEAP), is associated with kidney function decline in kidney transplant recipients (KTR) and to what extent this association is mediated by variation in venous bicarbonate (HCO3-). Method We used data from 642 KTR with a functioning graft ≥1 year after transplantation who were enrolled in the Transplantlines Food & Nutrition Cohort Study between 2008-2011. We applied the Frassetto equation (NEAP = (54.5 X protein (g/d) / potassium (mEq/d) - 10.2)) to calculate NEAPFFQ using intake reported in food frequency questionnaires and NEAPUrine from assessments of 24 hours urinary urea and potassium excretion. Patients were divided into tertiles of NEAP and differences across tertiles were analyzed by ANOVA, Kruskall-Wallis and Chi-Square tests, as appropriate. Cox regression models were used to study the associations between NEAPFFQ and NEAPUrine (both continuous variables and categories) with the composite endpoint kidney function decline, defined as doubling of serum creatinine or graft failure. Mediation analyses were performed to evaluate whether these associations were explained by venous bicarbonate. Results Mean age was 53±13 years, 56.1% were men, and mean eGFR was 52±20 ml/min/1.73m2. Patients within the highest tertile of NEAPFFQ were younger (P=0.04), more recently transplanted (P=0.002), consumed less fruit and vegetables (P<0.001), more fish (P=0.001), less alcohol (P=0.01), more meat (P<0.001) and had lower serum HCO3- concentration (P=0.02). During a median follow-up time of 5.3 (4.1-6.0) years, 121 (18.8%) patients developed kidney function decline. In multivariable Cox regression analysis, higher NEAPFFQ (per SD increase) was associated with increased risk of kidney function decline, independent of potential confounders, including age, sex, BMI, time after transplantation, primary kidney disease, eGFR and proteinuria (adjusted HR 1.30; 95%CI 1.10-1.53, P=0.002). Compared to patients in the lowest NEAPFFQ tertile, those in the highest tertile had a >1.5 higher risk of kidney function decline (adjusted HR 1.67; 95%CI 1.07-2.62, P=0.03). We observed similar results using NEAPUrine as the study exposure (adjusted HR 1.46 per SD increase; 95%CI 1.24-1.73, P<0.001; adjusted HR 1.99; 95%CI 1.24-3.18, P=0.004 for patients in the highest versus lowest tertile of NEAPUrine). These associations between NEAPFFQ (Figure A) and NEAPUrine (Figure B) with kidney function decline were visualized by fitting multivariable Cox regression models based on restricted cubic splines. Mediation analyses estimated that venous HCO3- at baseline mediated 19.3% (P=0.008) of the association between NEAPFFQ and kidney function decline and 26.5% (P=0.002) of the association between NEAPUrine with kidney function decline. Conclusion Higher NEAP is associated with a higher risk for kidney function decline in KTR, and this association was in part mediated by venous HCO3-. We speculate that reducing dietary acid load might mitigate the risk of kidney function decline in KTR.

Urinary metabolites associate with the rate of kidney function decline in patients with autosomal dominant polycystic kidney disease

BackgroundThe variable course of autosomal dominant polycystic kidney disease (ADPKD), and the advent of renoprotective treatment require early risk stratification. We applied urinary metabolomics to explore differences associated with estimated glomerular filtration rate (eGFR; CKD-EPI equation) and future eGFR decline.MethodsTargeted, quantitative metabolic profiling (1H NMR-spectroscopy) was performed on baseline spot urine samples obtained from 501 patients with ADPKD. The discovery cohort consisted of 338 patients (56% female, median values for age 46 [IQR 38 to 52] years, eGFR 62 [IQR 45 to 85] ml/min/1.73m2, follow-up time 2.5 [range 1 to 3] years, and annual eGFR slope –3.3 [IQR –5.3 to –1.3] ml/min/1.73m2/year). An independent cohort (n = 163) was used for validation. Multivariate modelling and linear regression were used to analyze the associations between urinary metabolites and eGFR, and eGFR decline over time.ResultsTwenty-nine known urinary metabolites were quantified from the spectra using a semi-automatic quantification routine. The model optimization routine resulted in four metabolites that most strongly associated with actual eGFR in the discovery cohort (F = 128.9, P = 7×10−54, R2 = 0.724). A model using the ratio of two other metabolites, urinary alanine/citrate, showed the best association with future annual change in eGFR (F = 51.07, P = 7.26×10−12, R2 = 0.150). This association remained significant after adjustment for clinical risk markers including height-adjusted total kidney volume (htTKV). Results were confirmed in the validation cohort.ConclusionsQuantitative NMR profiling identified urinary metabolic markers that associated with actual eGFR and future rate of eGFR decline. The urinary alanine/citrate ratio showed additional value beyond conventional risk markers.

Metabolomic Markers of Kidney Function Decline in Patients With Diabetes: Evidence From the Chronic Renal Insufficiency Cohort (CRIC) Study

Biomarkers that provide reliable evidence of future diabetic kidney disease (DKD) are needed to improve disease management. In a cross-sectional study, we previously identified 13 urine metabolites that had levels reduced in DKD compared with healthy controls. We evaluated associations of these 13 metabolites with future DKD progression. Prospective cohort. 1,001 Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes with estimated glomerular filtration rates (eGFRs) between 20 and 70mL/min/1.73m2 were followed up prospectively for a median of 8 (range, 2-10) years. 13 urine metabolites, age, race, sex, smoked more than 100 cigarettes in lifetime, body mass index, hemoglobin A1c level, blood pressure, urinary albumin, and eGFR. Annual eGFR slope and time to incident kidney failure with replacement therapy (KFRT; ie, initiation of dialysis or receipt of transplant). Several clinical metabolite models were developed for eGFR slope as the outcome using stepwise selection and penalized regression, and further tested on the time-to-KFRT outcome. A best cross-validated (final) prognostic model was selected based on high prediction accuracy for eGFR slope and high concordance statistic for incident KFRT. During follow-up, mean eGFR slope was-1.83±1.92 (SD) mL/min/1.73m2 per year; 359 (36%) participants experienced KFRT. Median time to KFRT was 7.45 years from the time of entry to the CRIC Study. In our final model, after adjusting for clinical variables, levels of metabolites 3-hydroxyisobutyrate (3-HIBA) and 3-methylcrotonyglycine had a significant negative association with eGFR slope, whereas citric and aconitic acid were positively associated. Further, 3-HIBA and aconitic acid levels were associated with higher and lower risk for KFRT, respectively (HRs of 2.34 [95% CI, 1.51-3.62] and 0.70 [95% CI, 0.51-0.95]). Subgroups for whom metabolite signatures may not be optimal, nontargeted metabolomics by flow-injection analysis, and 2-stage modeling approaches. Urine metabolites may offer insights into DKD progression. If replicated in future studies, aconitic acid and 3-HIBA could identify individuals with diabetes at high risk for GFR decline, potentially leading to improved clinical care and targeted therapies.

A metabolomics-based molecular pathway analysis of how the sodium-glucose co-transporter-2 inhibitor dapagliflozin may slow kidney function decline in patients with diabetes.

AimTo investigate which metabolic pathways are targeted by the sodium‐glucose co‐transporter‐2 inhibitor dapagliflozin to explore the molecular processes involved in its renal protective effects.MethodsAn unbiased mass spectrometry plasma metabolomics assay was performed on baseline and follow‐up (week 12) samples from the EFFECT II trial in patients with type 2 diabetes with non‐alcoholic fatty liver disease receiving dapagliflozin 10 mg/day (n = 19) or placebo (n = 6). Transcriptomic signatures from tubular compartments were identified from kidney biopsies collected from patients with diabetic kidney disease (DKD) (n = 17) and healthy controls (n = 30) from the European Renal cDNA Biobank. Serum metabolites that significantly changed after 12 weeks of dapagliflozin were mapped to a metabolite‐protein interaction network. These proteins were then linked with intra‐renal transcripts that were associated with DKD or estimated glomerular filtration rate (eGFR). The impacted metabolites and their protein‐coding transcripts were analysed for enriched pathways.ResultsOf all measured (n = 812) metabolites, 108 changed (P < 0.05) during dapagliflozin treatment and 74 could be linked to 367 unique proteins/genes. Intra‐renal mRNA expression analysis of the genes encoding the metabolite‐associated proteins using kidney biopsies resulted in 105 genes that were significantly associated with eGFR in patients with DKD, and 135 genes that were differentially expressed between patients with DKD and controls. The combination of metabolites and transcripts identified four enriched pathways that were affected by dapagliflozin and associated with eGFR: glycine degradation (mitochondrial function), TCA cycle II (energy metabolism), L‐carnitine biosynthesis (energy metabolism) and superpathway of citrulline metabolism (nitric oxide synthase and endothelial function).ConclusionThe observed molecular pathways targeted by dapagliflozin and associated with DKD suggest that modifying molecular processes related to energy metabolism, mitochondrial function and endothelial function may contribute to its renal protective effect.

Increased circulating galectin-1 levels are associated with the progression of kidney function decline in patients undergoing coronary angiography

Galectin-1 modulates acute and chronic inflammation, and is associated with glucose homeostasis and chronic renal disease. Whether the serum galectin-1 level can predict short-term and long-term renal outcomes after contrast exposure in patients undergoing coronary angiography (CAG) remains uncertain. This study aimed to evaluate the relationship between the serum galectin-1 level and the incidence of contrast-induced nephropathy (CIN), and to investigate the predictive role of the circulating galectin-1 level for renal function decline in patients undergoing CAG. In total, 798 patients who had undergone CAG were enrolled. Baseline creatinine and serum galectin-1 levels were determined before CAG. CIN was defined as an increase in the serum creatinine level of 0.5 mg/dl or a 25% increase from baseline within 48 h after the procedure, and renal function decline was defined as > 30% reduction of the estimated glomerular filtration rate from baseline. All patients were followed for at least 1 year or until the occurrence of death after CAG. Overall, CIN occurred in 41 (5.1%) patients. During a median follow-up period of 1.4 ± 1.1 years, 80 (10.0%) cases showed subsequent renal function decline. After adjustment for demographic characteristics, kidney function, traditional risk factors, and medications, higher galectin-1 levels were found to be associated independently with a greater risk of renal function decline [tertile 2: hazard ratio (HR) 5.56, 95% confidence interval (CI) 1.79–17.22; tertile 3: HR 5.56, 95% CI 1.97–16.32], but not with CIN, regardless of the presence of diabetes. In conclusion, higher baseline serum galectin-1 levels were associated with a greater risk of renal function decline in patients undergoing CAG, but were not associated independently with CIN.

Kidney Function Decline among Black Patients with Sickle Cell Trait and Sickle Cell Disease: An Observational Cohort Study.

Sickle cell trait and sickle cell disease are thought to be independent risk factors for CKD, but the trajectory and predictors of kidney function decline in patients with these phenotypes are not well understood. Our multicenter, observational study used registry data (collected January 2005 through June 2018) and included adult black patients with sickle cell trait or disease (exposures) or normal hemoglobin phenotype (reference) status (ascertained by electrophoresis) and at least 1 year of follow-up and three eGFR values. We used linear mixed models to evaluate the difference in the mean change in eGFR per year. We identified 1251 patients with sickle cell trait, 230 with sickle cell disease, and 8729 reference patients, with a median follow-up of 8 years. After adjustment, eGFR declined significantly faster in patients with sickle cell trait or sickle cell disease compared with reference patients; it also declined significantly faster in patients with sickle cell disease than in patients with sickle cell trait. Male sex, diabetes mellitus, and baseline eGFR ≥90 ml/min per 1.73 m2 were associated with faster eGFR decline for both phenotypes. In sickle cell trait, low hemoglobin S and elevated hemoglobin A were associated with faster eGFR decline, but elevated hemoglobins F and A2 were renoprotective. Sickle cell trait and disease are associated with faster eGFR decline in black patients, with faster decline in sickle cell disease. Low hemoglobin S was associated with faster eGFR decline in sickle cell trait but may be confounded by concurrent hemoglobinopathies. Prospective and mechanistic studies are needed to develop best practices to attenuate eGFR decline in such patients.

Association Between Dietary Patterns and Kidney Function in Patients With Chronic Kidney Disease: A Cross-Sectional Analysis of the German Chronic Kidney Disease Study

In the general population, "healthy" dietary patterns are associated with improved health outcomes, but data on associations between observance of specific dietary patterns and kidney function in patients with chronic kidney disease (CKD) are sparse. Dietary intake was evaluated using food frequency questionnaires in patients with moderately severe CKD under nephrology care enrolled into the observational multicenter German CKD study. The Dietary Approaches to Stop Hypertension (DASH) diet score, Mediterranean diet score, and German Food Pyramid Index (GFPI) were calculated and their association with estimated glomerular filtration rate (eGFR) and albuminuria was assessed by multivariable linear regression analysis, adjusted for gender, age, body mass index, energy intake, smoking status, alcohol intake, education, high-density lipoprotein-cholesterol (HDL- cholesterol), low-density lipoprotein-cholesterol (LDL-cholesterol), hypertension, and diabetes mellitus. A total of 2,813 patients (41% women; age 60.1±11.6years) were included in the analysis. High DASH diet score and GFPI were associated with lower systolic blood pressure and lower intake of antihypertensive medication, higher HDL, and lower uric acid levels. Mediterranean-style diet was associated with lower prevalence of diabetes mellitus. Higher DASH and Mediterranean diet scores were associated with higher eGFR (β-coefficient=1.226, P < .001; β-coefficient=0.932, P=.007, respectively). In contrast, GFPI was not associated with eGFR. For the individual components of the dietary patterns, higher intake of nuts and legumes, cereals, fish, and polyunsaturated fats was associated with higher eGFR and higher intake of dairy, composed of low- and whole-fat dairy, was associated with lower eGFR. No association was found between dietary patterns and albuminuria. Higher observance of the DASH or Mediterranean diet, but not German food pyramid recommendations, was associated with higher eGFR among patients with CKD. Improving dietary habits may offer an opportunity to better control comorbidities and kidney function decline in patients with CKD.

P1585Increased circulating galectin 1 level is associated with progression of kidney function decline in patients with suspected coronary artery disease, independent of diabetes

Abstract Background Galectin-1 modulates acute and chronic inflammation, and is associated with glucose homeostasis and chronic renal disease. Whether serum Galectin-1 levels could predict the short-term and long-term renal outcomes after contrast exposure in patients with suspected coronary artery disease remains uncertain. Purpose This study aimed to evaluate the relationship between serum Galectin-1 levels and the incidence of contrast-induced nephropathy and to investigate the predictive role of circulating galectin-1 levels in renal function decline in patients undergoing coronary angiography. Methods In total, 798 patients who had received coronary angiography were enrolled. Serum galectin-1 levels were determined before administration of contrast media. Contrast-induced nephropathy was defined as a rise in serum creatinine of 0.5 mg/dL or a 25% increase from baseline within 48 h after the procedure. Progressive renal function decline was defined as &gt;30% decrease in estimated glomerular filtration rate after discharge. All patients were followed up for at least one year or until the occurrence of death after coronary angiography. Results Overall, contrast-induced nephropathy occurred in 41 (5.1%) patients. During a median follow-up of 1.4±1.1 years, 80 (10.0%) cases had subsequent decline in renal function. After adjustment for demographic characteristics, kidney function, traditional risk factors, and medications, higher galectin-1 level was found to be independently associated with a higher risk for mortality and renal function decline (tertile 2, HR=3.12 95% CI,1.25–7.78; tertile 3, HR=3.25, 95% CI,1.42–7.41) but not for contrast-induced nephropathy, regardless of the presence of diabetes. Conclusions Higher baseline serum galectin-1 levels were associated with a higher risk of mortality and renal function decline in patients undergoing coronary angiography. Galectin-1 may play a pivotal role in progressive renal dysfunction, but further studies are needed to verify these results. Acknowledgement/Funding Ministry of Science and Technology of Taiwan (MOST 104-2314-B-075-047), Taipei Veterans General Hospital (V105C-0207, V106C-045, V108C-195)

Direct-acting antiviral therapy slows kidney function decline in patients with Hepatitis C virus infection and chronic kidney disease

Hepatitis C virus (HCV) infection is common and can accelerate chronic kidney disease (CKD) progression. Direct-acting antiviral (DAA) therapies against hepatitis C have consistently shown rates of sustained viral remission. However, the effect on kidney function is unknown. In a retrospective observational cohort study of HCV-infected patients receiving DAA therapies from 2013 to 2017, the slopes of estimated glomerular filtration rate (eGFR) decline were compared in the three years before DAA therapy to the slope after therapy. Pre- and post-treatment albuminuria values were also compared. In all, 1,178 patients were included; mean age of 56, 64% male, 71% white, 21% were diabetic, and 42% with cirrhosis. In patients with eGFR less than 60ml/min per 1.73m2, the annual decline in eGFR in the three years prior to treatment was -5.98 ml/min per year (95% confidence interval -7.30 to -4.67) and improved to -1.32 ml/min per year (95% confidence interval -4.50 to 1.88) after DAA therapy. In patients with eGFR greater than 60ml/min per 1.73m2 the annual decline in eGFR in the three years prior to treatment was -1.43 ml/min per year (95% confidence interval -1.78 to -1.08) and after DAA therapy was -2.32 ml/min per year (95% confidence interval -3.36 to -1.03). Albuminuria improved significantly in patients without diabetes, but not in those with diabetes. Predictors of eGFR improvement included having CKD at baseline and being non-diabetic. Events of acute kidney injury were rare, occurring in 29 patients, and unrelated to antiviral therapy in 76% of cases. Thus, DAA therapy for HCVs infection may slow CKD progression.

Exposure to vitamin k antagonists and kidney function decline in patients with atrial fibrillation and chronic kidney disease

BackgroundExposure to vitamin K antagonists (VKA) has been suggested to accelerate progression of chronic kidney disease (CKD) but robust clinical data are currently lacking. MethodsWe retrospectively evaluated the impact of VKA exposure on kidney function in patients with atrial fibrillation (AF) and CKD stage 3/4. Patients were prospectively followed within a primary care electronic database (median follow‐up of 1.45 years). The kidney function trajectory over time, defined as the annualized change in estimated glomerular filtration rate (eGFR), was analyzed with linear mixed‐effects regression including propensity score adjustment. Results14 432 patients (median age 78 years, median CHA2DS2‐VASc score 4 points) contributed 97 792 eGFR measurements (mean 6.8 measurements/patient; range: 1‐197). Mean baseline eGFR was 50.3 mL/min/1.73 m2; and declined by 1.10 mL/min/1.73 m2/year (95% CI: 0.91‐1.28, P<0.0001). In 7409 patients with VKA exposure, CKD progression was significantly faster compared to patients without VKA exposure (5‐year absolute eGFR loss from baseline: 6.0 mL/min/1.73 m2 vs 4.5 mL/min/1.73 m2, for an absolute 5‐year excess eGFR decline with VKA exposure of 1.5 mL/min/1.73 m2 (95% CI: 0.4‐2.7, P = 0.002). These results prevailed upon adjusting for CHA2DS2‐VASc score and other potential imbalances in prognostic variables, and in several sensitivity analyses. In the group without documented VKA exposure, 1775 VKA patients (24%) and 1012 patients (14%) developed a 30% decline in eGFR during follow‐up (P<0.0001). ConclusionsIn patients with AF and CKD, VKA use is associated with accelerated eGFR decline. Within the limitations of a retrospective analysis, this finding supports the “VKA‐renal‐calcification hypothesis.” However, although statistically significant, the excess loss in eGFR over 5 years with VKA was modest.

Plasma endostatin predicts kidney outcomes in patients with type 2 diabetes

Novel biomarkers are needed to predict kidney function decline in patients with type 2 diabetes, especially those with preserved glomerular filtration rate (GFR). There are limited data on the association of markers of endothelial dysfunction with longitudinal GFR decline. We used banked specimens from a nested case-control study in the Action to Control Cardiovascular Disease (ACCORD) trial (n=187 cases: 187 controls) and from a diverse contemporary cohort of type 2 diabetic patients from the Mount Sinai BioMe Biobank (n=871) to assess the association of plasma endostatin and kidney outcomes. We measured plasma endostatin at enrollment and examined its association with a composite kidney outcome of sustained 40% decline in estimated GFR or end-stage renal disease. Baseline plasma endostatin levels were higher in participants with the composite outcome. Each log2 increment in plasma endostatin was associated with approximately 2.5-fold higher risk of the kidney outcome (adjusted odds ratio [OR] 2.5; 95% confidence interval [CI] 1.5-4.3 in ACCORD and adjusted hazard ratio [HR] 2.6; 95% CI 1.8-3.8 in BioMe). Participants in the highest vs. lowest quartile of plasma endostatin had approximately four-fold higher risk for the kidney outcome (adjusted OR 3.6; 95% CI 1.8-7.3 in ACCORD and adjusted HR 4.4; 95% CI 2.3-8.5 in BioMe). The AUC for the kidney outcome improved from 0.74 to 0.77 in BioMe with the addition of endostatin to a base clinical model. Plasma endostatin was strongly associated with kidney outcomes in type 2 diabetics with preserved eGFR and improved risk discrimination over traditional predictors.

Determinants of Urine Volume in ADPKD Patients Using the Vasopressin V2 Receptor Antagonist Tolvaptan

The vasopressin V2 receptor antagonist (V2RA) tolvaptan is the first drug that has been shown to slow the rate of kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD). However, V2RAs also cause polyuria, with urine output that averages 6L/d. We assessed determinants of urine volume in patients with ADPKD using V2RAs because such information may help develop strategies to improve V2RA tolerability. Clinical trial of patients with ADPKD studied at baseline, after 3 weeks of V2RA treatment (tolvaptan, 90/30mg, in the last week), and after a 3-week washout period. The trial included patients with ADPKD with a wide range of kidney function (measured glomerular filtration rates [mGFRs]; range, 18-148mL/min/1.73m2). Tolvaptan treatment for 3 weeks. 24-hour urine volume. Multivariable regression analysis with stepwise backward elimination was performed both during and without V2RA treatment to evaluate the influence of 24-hour osmolar excretion, mGFR, and total kidney volume on associations between tolvaptan and urine volume. Included were 27 patients (48% men, aged 46±9.8 years with mGFRs of 61±35mL/min/1.73m2). V2RA treatment caused a median increase in urine volume of 128% (interquartile range, 75%-202%), to 5,930±1,790mL. 24-hour osmolar excretion was strongly associated with 24-hour urine volume (standardized β= 0.73; P< 0.001). During V2RA use, no independent associations were detected between 24-hour urine volume and mGFR, total kidney volume, or V2RA concentration. Limited sample size, no standardized diets. Osmolar excretion is the major determinant of urine volume in patients taking V2RAs as a consequence of the inability to concentrate urine. Restriction of osmolar intake may therefore limit V2RA-induced polyuria, giving patients more control over the aquaretic side effects and improving the tolerability of these drugs.

Altered Hepatobiliary Disposition of Tolvaptan and Selected Tolvaptan Metabolites in a Rodent Model of Polycystic Kidney Disease.

Tolvaptan, a vasopressin V2-receptor antagonist, has demonstrated efficacy in slowing kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD). In the pivotal clinical trial, the incidence of elevated liver enzymes was higher in patients receiving tolvaptan compared with placebo. Adjudication by a panel of expert hepatologists concluded a causal link of tolvaptan to liver injury in patients with ADPKD. An ex situ isolated perfused liver (IPL) study of tolvaptan disposition was undertaken in a rodent model of ADPKD, the polycystic kidney (PCK) rat (n = 5), and compared with wild-type (WT) Sprague-Dawley rats (n = 6). Livers were perfused with tolvaptan, followed by a tolvaptan-free washout phase. Total recovery (mean ± S.D. percentage of dose; PCK vs. WT) of tolvaptan and two metabolites, DM-4103 and DM-4107, quantified by liquid chromatography-tandem mass spectroscopy, was 58.14% ± 24.72% vs. 43.40% ± 18.11% in liver, 20.10% ± 9.15% vs. 21.17% ± 12.51% in outflow perfusate, and 0.08% ± 0.01% vs. 0.39% ± 0.32% in bile. DM-4103 recovery (mean ± S.D. percentage of dose) was decreased in PCK vs. WT bile (<0.01% ± <0.01% vs. 0.02% ± 0.01%; P = 0.0037), and DM-4107 recovery was increased in PCK vs. WT outflow perfusate (1.60% ± 0.57% vs. 0.43% ± 0.29%; P = 0.0017). A pharmacokinetic compartmental model assuming first-order processes was developed to describe the rate vs. time profiles of tolvaptan and DM-4103 + DM-4107 in rat IPLs. The model-derived estimate of tolvaptan's biliary clearance was significantly decreased in PCK compared with WT IPLs. The model predicted greater hepatocellular concentrations of tolvaptan and DM-4103 + DM-4107 in PCK compared with WT IPLs. Increased hepatocellular exposure to tolvaptan and metabolites may contribute to the hepatotoxicity in patients with ADPKD treated with tolvaptan.

Sclerostin Serum Concentration in Patients with Predialysis Ckd Stage 3-5

Sclerostin is a glycoprotein expressed by osteocytes and plays a role in bone turnover in themetabolism of the bone. Sclerostin blocks the formation of a ligand with its receptor on theWnt/β-catenin pathway, and influences the activity of osteoblasts. Sclerostin also influencesmineral and bone disturbances in CKD via the interaction between kidney, bone and vascularaxis. The concentration of sclerostin will rise especially in patients with ESRD undergoingdialysis. Concentration of sclerostin has not been reported yet in non-dialysis CKD patientstage 3-5 and the aim of this study is to see sclerostin concentration on those population. Methods This is a descriptive and cross-sectional study designed to measure sclerostinconcentration in non dialysis patients with CKD stage 3-5. The sclerostin concentration ismeasured using an enzyme-linked immunosorbent assay kit. CKD stages are diagnosed usingthe KDIGO-2012 criteria which measures the estimated GFR (eGFR) with the formulation of EPICKD. Fifty six patients with CKD stage 3-5 were enrolled in this study and one way ANOVA comparative test followed with a post hoc analysis using Benferroni test to analysethe data. Results The mean concentration level of serum sclerostin in this population is (79.7+ 41.2) pmol/L, and in patients with CKD stage 3, CKD stage 4, and CKD stage 5 are (59.6 +28.5) pmol/L, (71.9 + 42.2) pmol/L and (96.7 + 39.8) pmol/L respectively. The comparativetest of mean concentrations of the serum sclerostin between stages of CKD are statisticallysignificant with a p=0.022. The post hoc analysis of serum sclerostin concentration betweenCKD stage 3 and CKD stage 5 have a significant difference with a mean of 37 pmol/L andp=0.037. Conclusion, The serum sclerostin concentration rise in accordance with the declineof kidney function in patients with pre-dialysis CKD stage 3-5.

Empagliflozin and Kidney Function Decline in Patients with Type 2 Diabetes: A Slope Analysis from the EMPA-REG OUTCOME Trial.

Empagliflozin slowed the progression of CKD in patients with type 2 diabetes and cardiovascular disease in the EMPA-REG OUTCOME Trial. In a prespecified statistical approach, we assessed treatment differences in kidney function by analyzing slopes of eGFR changes. Participants (n=7020) were randomized (1:1:1) to empagliflozin 10 mg/d, empagliflozin 25 mg/d, or placebo added to standard of care. We calculated eGFR slopes using random-intercept/random-coefficient models for prespecified study periods: treatment initiation (baseline to week 4), chronic maintenance treatment (week 4 to last value on treatment), and post-treatment (last value on treatment to follow-up). Compared with placebo, empagliflozin was associated with uniform shifts in individual eGFR slopes across all periods. On treatment initiation, adjusted mean slope (eGFR change per week, ml/min per 1.73 m2) decreased with empagliflozin (-0.77; 95% confidence interval, -0.83 to -0.71; placebo: 0.01; 95% confidence interval, -0.08 to 0.10; P<0.001). However, annual mean slope (ml/min per 1.73 m2 per year) did not decline with empagliflozin during chronic treatment (empagliflozin: 0.23; 95% confidence interval, 0.05 to 0.40; placebo: -1.46; 95% confidence interval, -1.74 to -1.17; P<0.001). After drug cessation, the adjusted mean eGFR slope (ml/min per 1.73 m2 per week) increased and mean eGFR returned toward baseline level only in the empagliflozin group (0.56; 95% confidence interval, 0.49 to 0.62; placebo -0.02; 95% confidence interval, -0.12 to 0.08; P<0.001). Results were consistent across patient subgroups at higher CKD risk. The hemodynamic effects of empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function.

Kidney Function Decline in Patients with CKD and Untreated Hepatitis C Infection.

Studies evaluating the role of hepatitis C viral (HCV) infection on the progression of CKD are few and conflicting. Therefore, we evaluated the association of untreated HCV on kidney function decline in patients with stage 3-5 CKD. This retrospective cohort study included members of Kaiser Permanente Southern California and Kaiser Permanente Mid-Atlantic States aged ≥18 years, with incident HCV and CKD diagnoses from January 1, 2004 to December 31, 2014. We used generalized estimating equations to compare the rate of change in eGFR between those with HCV and CKD versus CKD alone, adjusting for covariates. Cox proportional hazards models compared the risk of 25% decrease in eGFR and ESKD (defined as progression to eGFR<15 ml/min per 1.73 m2 on two or more occasions, at least 90 days apart) in those with HCV and CKD versus CKD alone, adjusting for covariates. We identified 151,974 patients with CKD only and 1603 patients with HCV and CKD who met the study criteria. The adjusted annual decline of eGFR among patients with HCV and CKD was greater by 0.58 (95% confidence interval [95% CI], 0.31 to 0.84) ml/min per 1.73 m2, compared with that in the CKD-only population (HCV and CKD, -1.61; 95% CI, -1.87 to -1.35 ml/min; CKD only, -1.04; 95% CI, -1.06 to -1.01 ml/min). Adjusted for covariates, the hazard for a 25% decline in eGFR and for ESKD were 1.87 (95% CI, 1.75 to 2.00) and 1.93 (95% CI, 1.64 to 2.27) times higher among those with HCV and CKD, respectively, compared with those with CKD only. Untreated HCV infection was associated with greater kidney function decline in patients with stage 3-5 CKD.