Effects of Sacubitril/Valsartan vs Irbesartan on Urine Tubular Biomarkers in CKD: Findings from the UK HARP-III Trial.

Progression From Acute Kidney Injury to Chronic Kidney Disease: A Pediatric Perspective

Urinary Tubular Biomarkers of Kidney Damage: Potential Value in Clinical Practice

IntroductionCell-free deoxyribonucleic acid DNA (cf-DNA) in urine is promising due to the advantage of urine as an easily obtained and non-invasive sample source over tissue and blood. In clinical practice, it is important to identify non-invasive biomarkers of chronic kidney disease (CKD) in monitoring and surveillance of disease progression. Information is limited, however, regarding the relationship between urine and plasma cf-DNA and the renal outcome in CKD patients.MethodsOne hundred and thirty-one CKD patients were enrolled between January 2016 and September 2018. Baseline urine and plasma cell-free mitochondrial DNA (cf-mtDNA) and cell-free nuclear DNA (cf-nDNA) were isolated using quantitative real-time PCR. Estimated glomerular filtration rate (eGFR) measurement was performed at baseline and 6-month follow-up. Favorable renal outcome was defined as eGFR at 6 months minus baseline eGFR> = 0. Receiver operator characteristics (ROC) curve analysis was performed to assess different samples of cf-DNA to predict favorable renal outcomes at 6 months. A multivariate linear regression model was used to evaluate independent associations between possible predictors and different samples of cf-DNA.ResultsPatients with an advanced stage of CKD has significantly low plasma cf-nDNA and high plasma neutrophil gelatinase-associated lipocalin (NGAL) levels. Low urine cf-mtDNA, cf-nDNA levels and low plasma NGAL were significantly correlated with favorable renal outcomes at 6 months. The urine albumin-creatinine ratio (ACR) or urine protein-creatinine ratio (PCR) level is a robust predictor of cf-mtDNA and cf-nDNA in CKD patients. Baseline urine levels of cf-mtDNA and cf-nDNA could predict renal outcomes at 6 months.ConclusionsUrinary cf-mtDNA and cf-nDNA may provide novel prognostic biomarkers for renal outcome in CKD patients. The levels of plasma cf-nDNA and plasma NGAL are significantly correlated with the severity of CKD.

Chronic kidney disease (CKD) in children contributes to the global health burden. The focus on using novel biomarkers to predict the onset and progression of the disease has increased tremendously over the past decade. Discovery of these biomarkers offers prospects for the early anticipation of the late stages of CKD, slowing down disease progression, and achieving better disease outcomes. The aim of this article is to classify and highlight the utility of these novel biomarkers in predicting disease-onset and progression. Biomarkers of CKD are broadly classified into biomarkers of kidney function and biomarkers of kidney damage. Glomerular filtration rate (GFR) remains the most important marker of kidney function, but it cannot be easily measured in most clinical and research settings. Its estimating equations, therefore, depend on filtration biomarkers such as serum creatinine and serum cystatin C. For instance, the CKD-epidemiology collaboration equation has been suggested as the preferred prediction equation for the staging and classification of estimated GFR (eGFR) in CKD. Although albuminuria is the traditional biomarker of kidney damage, it precedes any decline in eGFR and may be absent in tubulointerstitial disease. Thus, more sensitive and specific novel biomarkers of kidney damage are emerging which hold prospects for earlier prediction of CKD in children. They have been classified as tubular and miscellaneous biomarkers. Tubular biomarkers are represented by markers such as kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, N-acetyl-ß-D glucosaminidase, liver-type fatty-acid binding protein, cystatin C and a-1-microglobulin. Miscellaneous biomarkers include monocyte chemoattractant protein-1, interleukin-18, and retinol binding protein 4. Despite their advantages over albuminuria, they still require validation before they can be applied in clinical practice.

Chronic kidney disease (CKD) is a major health and economic burden within Australia. Estimated glomerular filtration rate (eGFR) and albuminuria (Alb) are used to determine if a patient has CKD, but these routine clinical kidney function measurements are inadequate when predicting progressive CKD. This thesis addressed two themes: firstly, clinical CKD biobanking within Australia; and secondly, improving clinical and research outcomes for CKD patients by developing a prognostic clinical tool.Four aims were completed. i) To establish a clinical biobank, termed the CKD Biobank, within Queensland, Australia and develop this into a bioresource. 100 CKD patients, consisting of patients with diabetic nephropathy, vascular diseases, genetic kidney diseases, glomerulonephritis, and a range of other primary kidney diseases, were recruited. In approximately 80% of these patients, baseline bio-specimens were collected alongside clinical data.ii) To address the need for a better definition of progressive CKD and to identify a robust definition of progressive kidney function decline. A systematic review was conducted to identify definitions of progressive kidney function decline currently used in research. A range of definitions was identified and subsequently investigated within the CKD Queensland Registry. A ≥30% decline in eGFR from baseline was found to be robust in distinguishing between patients who experienced a progressive decline in kidney function and those who did not.iii) To use the CKD Queensland Registry and CKD Biobank to identify biomarkers of progressive CKD. Discovery-based and hypothesis-based approaches were used, within the CKD Queensland Registry and the CKD Biobank, respectively, to identify novel and emerging biomarkers of progressive CKD. Several biomarkers were identified that characterised the pathophysiological mechanisms of CKD, with varying capacity to distinguish between progressive and non-progressive CKD.iv) To develop a novel prognostic clinical tool, termed the “distinguishing risk of progressive CKD” (DROP CKD) tool, for differentiating between progressive and non-progressive CKD patients at baseline biomarker measurements. The DROP CKD tool was a predictive model calculated by linear discriminant analysis and constructed from biomarkers that differed between progressive and non-progressive CKD patients. A step-backwards approach was used for biomarker selection to maximise accuracy of the DROP CKD tool.Three hypotheses were investigated. i) A biobank, designed for a specific application that overcomes the ethics, governance, and quality control hurdles, will prove a valuable bioresource. The CKD Biobank has proved a useful bioresource, not only for this thesis, but for several other research projects. The CKD Biobank was utilised for investigating progressive CKD biomarkers and developing the DROP CKD tool for predicting progressive CKD. This Biobank was used, additionally, to supply bio-specimens from healthy controls for a discovery-based project to identify metabolites with prognostic capabilities in kidney cancer, and bio-specimens from diabetic nephropathy and glomerulonephritis CKD patients for research concerning presence of coagulation proteases in urine.ii) Progressive and non-progressive CKD will be characterised by biomarkers of kidney function, tissue injury, inflammation, oxidative stress, tissue repair, fibrosis, and comorbidities of CKD within the venous blood or urine of CKD patients. Compared to non-progressive patients, progressive patients of the CKD Queensland Registry and the CKD Biobank were characterised as having reduced kidney function, being anaemic, having an altered electrolyte-water balance, metabolic acidosis, dyslipidaemia, and as having mineral and bone disease. Progressive CKD patients of the CKD Biobank were further characterised by tissue injury, inflammation, and hypercoagulability while progressive CKD patients of the CKD Queensland Registry were only additionally characterised by eosinophilia.iii) A panel of the biomarkers, measured at baseline, will accurately predict progressive CKD. Biomarkers that were observed as differing between progressive and non-progressive CKD patients of the CKD Biobank were utilised to develop the DROP CKD tool. Through the step-backwards method, a biomarker panel consisting of eGFR, serum creatinine, cystatin-c, urea, tumour necrosis factor (TNF)-α, TNF Receptor-I, TNF Receptor-II, stem cell factor, tryptase, neutrophil gelatinase-associated lipocalin, tissue factor, bicarbonate, calculated osmolality, and haematocrit were observed as having an accuracy of 95.5% when predicting progressive CKD based on baseline biomarker expression. Moreover, the DROP CKD tool was more accurate than traditional kidney function measurements for determining progressive CKD.This thesis attempted to expand upon CKD biobanking capabilities and improve clinical and research outcomes for CKD patients by developing a novel prognostic clinical tool for predicting progression of CKD. Several avenues of research are still required to produce translatable results that will improve patient outcomes. Defining progressive CKD requires further investigation to identify a definition that robustly characterises a “progressive” decline in kidney function, accounting for the non-linear nature of eGFR decline and associating with meaningful clinical outcomes without underdiagnosing progression. Additional biomarker discovery is needed to identify novel biomarkers which can characterise progressive CKD. Finally, pre-existing and novel biomarkers need to be combined into a panel that can predict progressive CKD. This panel must be assayed in a minimally-invasive, efficient, manner, and communicate clinically-meaningful information to inform clinical management of CKD patients.

Introduction: Chronic kidney disease (CKD) is one of the most threatening and important disorders worldwide in both industrial and developing nations. In addition, neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid-binding protein (L-FABP), and kidney injury molecule-1 (KIM-1) are three factors suggested as diagnostic and prognostic biomarkers in CKDs. Considering the lack of enough efficiency of the creatinine in the prognosis of the CKD, the present study aimed to assess the relationship between these three factors and CKD occurrence and determine if they could be considered valid biomarkers in this regard. Materials and Methods: The present case-control study was designed enrolling 42 patients with confirmed CKD referring to the Imam Khomeini hospital of Kangan. The participants were 42 years old and gender-matched healthy counterparts. Blood samples were obtained, and then NGAL, KIM-1, and L-FABP were determined by the enzyme-linked immunosorbent assay using commercial kits (Bioassay Technology Laboratory). Finally, the serum creatinine was detected by applying Jaffe’s method. Results: Based on the results, significant differences were found in the serum levels of all four factors between CKD patients and the control group. More precisely, the serum levels of NGAL (P < 0.0001, specificity: 87.6%, sensitivity: 79.3%, and the area under the curve, AUC: 0.89), L-FABP (P < 0.0001, specificity: 83.3%, sensitivity: 78.3%, and AUC: 0.86), KIM-1 (P < 0.0001, specificity: 85.7%, sensitivity: 78.6%, and AUC: 0.88), and creatinine (P < 0.0001) were significantly higher in individuals with CKDs in comparison with controls. Eventually, the serum levels of NGAL, L-FABP, and KIM-1 were significantly correlated with each other in both patient and control groups (P < 0.0001). Conclusion: In general, NGAL, L-FABP, KIM-1, and creatinine could be used as independent biomarkers for the diagnosis of CKD. Moreover, the measurement of NGAL, L-FABP, and KIM-1 altogether could be a valid assessment for the diagnosis of CKD.

Background and Aims Proteinuria is not only a biomarker of chronic kidney disease (CKD) and a risk predictor of adverse outcomes but also a driver of kidney disease progression. The excessive filtration of plasma proteins through the glomerular filtration barrier exerts a toxic effect on tubular cells which ultimately leads to fibrosis and end-stage kidney disease (ESKD. The aim of this study was to assess the levels of various tubular biomarkers in both serum and urine in patients with biopsied glomerular and proteinuric kidney diseases, and correlate them with renal histology and kidney outcomes. Method A retrospective study and observational study was conducted at a single center from January 2016 to December 2021. Serum and urine samples were collected on the same day of renal biopsy and were correlated with histological data from a cohort of 156 patients with proteinuric kidney diseases. Kidney outcomes were registered during a median follow-up period of 26 months and defined as a decrease in eGFR ≥ 40% from baseline or the development of end-stage kidney disease. The following urinary markers, adjusted to urine creatinine, were analyzed: β2-mcg (beta 2 microglobulin), α1-mcg (alpha 1 microglobulin), NGAL (Neutrophil Gelatinase-Associated Lipocalin), uKIM-1 (Kidney Injury Molecule-1), MCP-1 (Monocyte Chemoattractant Protein-1), uDKK-3 (urinary Dickkopf-3), and uUMOD (uromodulin). Serum markers sKIM-1 and uUMOD were also collected. Results Regarding the etiology of proteinuric kidney disease, the majority corresponded to glomerular disease (68.6%) followed by diabetic kidney disease (12.8%). Higher levels of proteinuria were associated with increased values of β2-mcg and α1-mcg levels and low levels of uUMOD and sUMOD. A significant correlation between the extent of interstitial fibrosis and specific biomarkers was observed: uDKK3 (rho = 0.804, p < 0.001), sKIM-1 (rho = 0.472, p < 0.001), sUMOD (rho = −0.370, p < 0.001), uUMOD (rho = −0.317, p < 0.001), MCP-1 (rho = 0.374, p < 0.001), uKIM-1 (rho = 0.368, p < 0.001), and β2-mcg (rho = 0.392, p < 0.001). Multivariate regression analysis identified uDKK3 as an independent predictor of interstitial fibrosis (Beta 0.728, p < 0.001) adjusted for age, serum creatinine and proteinuria. Elevated levels of MCP-1 and uKIM-1 were associated with a higher risk of significant cortical interstitial inflammation >10% in the logistic regression analysis adjusted for eGFR, proteinuria, and microhematuria: MCP-1 OR = 5.14, 95% CI (2.27−11.62), p < 0.001 and uKIM-1 OR = 1.64, 95% CI (1.05−2.58), p = 0.031. Patients with higher tertiles of β2mcg, MCP1, uDKK3, and KIM1s, and lower tertiles of uUMOD and sUMOD experienced a significantly reduced renal event-free survival in the analysis of Kaplan-Meier model (Fig.). Moreover, of all the evaluated markers, uDKK3 was identified as the best predictor of renal events [HR = 1.03, 95% CI (1.01−1.06), p = 0.008], independently of age, baseline eGFR, proteinuria, and the extent of interstitial fibrosis at the time of renal biopsy. Conclusion Tubular biomarkers may offer prognostic value in proteinuric kidney diseases, particularly uDKK3, exhibiting a notable correlation with interstitial fibrosis and serving as a potential predictor of CKD progression.

Neutrophil gelatinase-associated lipocalin (NGAL) is considered one of the most informative biomarkers of chronic kidney disease (CKD). NGAL can also serve as a biomarker of cardiovascular disease and heart failure (HF). However, the relationship between systolic function and serum NGAL concentrations in patients with chronic HF (CHF) of ischemic origin remains insufficiently studied. The aim. To study the influence of tubulo-interstitial injury marker NGAL on systolic function in patients with CHF of ischemic origin. Materials and methods. The study included 51 patients with CHF, stage II AB, NYHA II-IV FC. Doppler echocardiographic examination was performed on the device Esaote MyLab Eight (Italy) according to standard methods. NGAL levels were analyzed using an ELISA kit (E-EL-H0096, Elabscience, USA). Depending to the concentration of serum NGAL, the patients were divided into 2 subgroups. In the first group (n = 37), the NGAL level was higher than 168 ng/ml, in the second (n = 14) – less than 168 ng/ml. Results. The mean serum NGAL concentration in the first subgroup was 192 (183; 200) ng/ml, in the second subgroup – 154 (134; 160) ng/ml. The patients with CHF of ischemic origin with tubulo-interstitial injury (according to the serum concentration of NGAL) did not differ significantly from the patients with CHF of ischemic origin without tubulo-interstitial injury in age (P = 0.950), height (P = 0.983), weight (P = 0.681), body surface area (P = 0.975). Most of left ventricular systolic function indicators showed a downward tendency (S 6.90 ± 2.85 cm/s vs. 7.67 ± 2.83 cm/s (P = 0.536); S lat 7.33 ± 2.08 cm/s vs. 11.00 ± 4.00 cm/s (P = 0.467); TEI LV 0.56 ± 0.26 c.u. vs. 0.49 ± 0.14 c.u. (P = 0.747)) in the patients with CHF of ischemic origin with elevated serum levels of NGAL compared to similar indicators in the patients with CHF of ischemic origin without tubulo-interstitial injury. The index of LVEF was significantly lower in the patients with CHF with elevated serum NGAL compared to that in the patients with CHF with normal serum NGAL (50.43 ± 17.85 % vs. 63.29 ± 13.24 % (P = 0.021)). Conclusions. Serum NGAL was not only the sensitive marker of tubulo-interstitial injury in patients with CHF of ischemic origin, but also appeared to be a predictor of changes in systolic heart function.

Proteinuria is not only a biomarker of chronic kidney disease (CKD) but also a driver of CKD progression. The aim of this study was to evaluate serum and urinary tubular biomarkers in patients with biopsied proteinuric kidney disease and to correlate them with histology and kidney outcomes. A single-center retrospective study was conducted on a cohort of 156 patients from January 2016 to December 2021. The following urinary and serum biomarkers were analyzed on the day of kidney biopsy: beta 2 microglobulin (β2-mcg), alpha 1 microglobulin (α1-mcg), neutrophil gelatinase-associated lipocalin (NGAL), urinary kidney injury molecule-1 (uKIM-1), monocyte chemoattractant protein-1 (MCP-1), urinary Dickkopf-3 (uDKK3), uromodulin (urinary uUMOD), serum kidney injury molecule-1 (sKIM-1) and serum uromodulin (sUMOD). A composite outcome of kidney progression or death was recorded during a median follow-up period of 26 months. Multivariate regression analysis identified sUMOD (β-0.357, P<.001) and uDKK3 (β 0.483, P<.001) as independent predictors of interstitial fibrosis, adjusted for age, estimated glomerular filtration rate (eGFR) and log proteinuria. Elevated levels of MCP-1 [odds ratio 15.61, 95% confidence interval (CI) 3.52-69.20] were associated with a higher risk of cortical interstitial inflammation >10% adjusted for eGFR, log proteinuria and microhematuria. Upper tertiles of uDKK3 were associated with greater eGFR decline during follow-up. Although not a predictor of the composite outcome, doubling of uDKK3 was a predictor of kidney events (hazard ratio 2.26, 95% CI 1.04-4.94) after adjustment for interstitial fibrosis, eGFR and proteinuria. Tubular markers may have prognostic value in proteinuric kidney disease, correlating with specific histologic parameters and identifying cases at higher risk of CKD progression.

Background: In Nicaragua, an excess prevalence of chronic kidney disease (CKD) of unknown etiology has been described in young, male agricultural workers, particularly in sugarcane workers. Many potential causes have been hypothesized, including exposures to extreme heat and heavy metals, but the etiologic agent remains unknown and it is unclear whether the disease results from occupational or nonoccupational factors. Our aims include characterizing the type of kidney damage, evaluating occupational factors, and investigating the role of metals exposure. Methods: Our study population included 284 sugarcane workers representing 7 different job tasks. Blood and urine samples were collected during two rounds of sampling, at the beginning and end of the 6-month harvest season (zafra). We analyzed biological samples for cadmium, uranium, and arsenic (in urine); lead (in blood); and biomarkers of kidney injury and CKD. Results: Estimated glomerular filtration rate (eGFR) was significantly different by sugarcane job and decreased by 6.4 mL/min/1.73 m2 during the zafra in cane cutters as compared to factory workers (p=0.006). Similarly, urine NGAL differed by job, increasing most among cane cutters, by 19.2 mg/g creatinine, as compared to factory workers (p=0.04). Generally, urine albumin was low in all workers. Heavy metals were not associated with markers of kidney function, with the exception of arsenic; workers with the highest urinary arsenic levels had significantly lower eGFR (p=0.01). Conclusions: Biomarkers of kidney injury and CKD were highest among cane cutters and lowest among factory workers, supporting the hypothesis that workers performing the most intensive physical labor in the hottest conditions are at greater risk of developing CKD. The absence of albuminuria suggests a tubulointerstitial, not glomerular, disease. Finally, there is some evidence that high exposure to arsenic is associated with biomarkers of CKD.

Angiotensin Blockage with Losartan Is Associated with Decreased Albuminuria and Stable Renal Function in Adults and Children with HbSS on Hydroxyurea

Association between plasma and urinary orosomucoid and chronic kidney disease in adults with sickle cell disease.

Background— In patients with heart failure, renal dysfunction is associated with a poor outcome. We aimed to assess the prognostic value of plasma neutrophil gelatinase–associated lipocalin (NGAL), a novel marker of renal tubular damage, in patients with heart failure with or without renal dysfunction, and compare it with 2 frequently used biomarkers of chronic kidney disease. Methods and Results— Plasma NGAL, estimated glomerular filtration rate (eGFR), and cystatin C were assessed in 562 patients with heart failure. Chronic kidney disease was defined as eGFR&lt;60 mL/min per 1.73 m 2 . Outcome was all-cause mortality at 36 months. Mean age was 71±11 years, 61% were men, and 97% were in New York Heart Association functional class II/III. Mean baseline eGFR was 54±20 mL/min per 1.73 m 2 , mean cystatin C was 11.2 (7.7–16.2) mg/L, and median plasma NGAL was 85 (60–123) ng/mL. Higher plasma NGAL levels were independently associated with an increased risk of all-cause mortality, in patients with and without chronic kidney disease (hazard ratio [per SD increase in log NGAL]=1.45 [1.22–1.72]; P &lt;0.001 and hazard ratio=1.51 [1.06–2.16]; P =0.023, respectively). Similarly, both in patients with high and low cystatin C (median cut-off), higher plasma NGAL levels were independently associated with an increased risk of all-cause mortality. Moreover, when NGAL was entered in the multivariable risk prediction model, eGFR ( P =0.616) and cystatin C ( P =0.937) were no longer associated with mortality. Conclusions— Plasma NGAL predicts mortality in patients with heart failure, both in patients with and without chronic kidney disease and is a stronger predictor for mortality than the established renal function indices eGFR and cystatin C.

Our study aims to evaluate the prevalence of elevated cardiac biomarkers, as well as their associations with chronic kidney disease (CKD) and long-term risk of mortality (all-cause and cardiovascular) in the US individuals without known cardiovascular disease. The study population was derived from individuals aged ≥ 20 years in NHANES 1999 to 2004. We calculated the prevalence of elevated cardiac biomarkers in both CKD and non-CKD populations and used multivariable logistic regression to assess the relationships between each cardiac biomarker and CKD. We also used multivariable Cox proportional hazards models and competing risk models to evaluate the adjusted associations between elevated cardiac biomarkers and all-cause and cardiovascular mortality. The crude prevalence of CKD in the overall population was 14.71%. Among CKD individuals, the age-standardized prevalence of elevated NT-ProBNP (≥ 125 pg/mL), hs-cTnT (≥ 6 ng/L), and hs-cTnI (M ≥ 6 ng/L and F ≥ 4 ng/L) were 26.43%, 47.44%, and 19.23%, respectively. After adjusting for cardiovascular and renal risk factors, significant correlations were observed between elevated cardiac biomarkers with CKD. Analysis of follow-up data revealed elevated cardiac biomarkers were independently associated with cumulative occurrence of all-cause mortality (CKD: adjusted hazard ratio [HR]: NT-proBNP: 2.00 [95% CI, 1.56–2.56]; hs-cTnT: 2.89 [95% CI, 1.96–4.26]; hs-cTnI: 1.92 [95% CI, 1.50–2.44]) and cardiovascular mortality (CKD: adjusted hazard ratio [HR]: NT-proBNP: 2.38 [95% CI, 1.61–3.51]; hs-cTnT: 2.70 [95% CI, 1.35–5.40]; hs-cTnI: 2.11 [95% CI, 1.46–3.04]). Additionally, different detection methodologies (Abbott, Siemens, Ortho) do not significantly affect the correlation between hs-cTnI and CKD, with a consistent positive correlation observed. Our research evaluated the substantial burden of elevated cardiac biomarkers in CKD individuals and provided crucial prognostic information regarding the long-term risk of mortality. These findings will offer significant guidance for risk stratification and the formulation of tailored prevention strategies across diverse populations.

The prevalence and identification of chronic kidney disease in Switzerland