Marker Of Kidney Disease Progression Research Articles

Plasma Proteomics of Renal Function: A Trans-ethnic Meta-analysis and Mendelian Randomization Study.

Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. A cross-sectional study of 993 plasma proteins among 2,882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified trans-ethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR . Fifty-seven plasma proteins were associated with eGFR, including one novel protein. Twenty-three of these were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. In a discovery-replication setting, we identified 57 proteins trans-ethnically associated with eGFR. The revealed causal relationships are an important stepping-stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.

MO224VCAM-1 LEVELS ASSOCIATED WITH ALBUMINURIA IN MULTIBACILLARY LEPROSY

Abstract Background and Aims Leprosy may present important renal and endothelial abnormalities, and this can worse patients’ prognosis. However, renal and vascular involvement in these patients has been poor investigated. The aim of this study was to investigate if higher systemic endothelial biomarkers levels are associated with renal abnormalities and clinical aspects of leprosy. Method This is a cross-sectional study with leprosy patients before initiation of multidrug therapy enrolled in January 2017 to December 2018 in Fortaleza, northeast Brazil. Leprosy-associated clinical and epidemiological data were collected. Two groups were constructed: Paucibacillary (PB) and Multibacillary (MB) for comparisons. Serum and urine samples were obtained for laboratory analysis. In urine the following parameters were evaluated: creatinine, proteinuria and albuminuria. In serum the endothelial biomarkers were evaluated: VCAM-1 and ICAM-1, using ELISA assay. Results A total of 101 leprosy patients were included, with mean age of 48±15 years, and 71 (70%) were male. The multibacillary form occurred in 81 cases (80%), where 22 had a Virchowian form. VCAM-1 was elevated in MB group and was correlated with the bacteriological index (skin smear) (r = 0.372, p <0.01), duration of disease symptoms (r = 0.234, p = 0.04), and number of skin lesions ( r = 0.331, p <0.001). Moreover, in MB patients who presented albuminuria >15 mg/g of creatinine, VCAM-1 showed a significant correlation (r = 0.341, p <0.05) with increased albuminuria and improve the correlation with number of skin lesions (r = 0.653, p=0.003). Conclusion Multibacillary leprosy patients present high systemic levels of VCAM-1, associated with leprosy clinical features and increased albuminuria, an important marker of kidney disease progression. Further prospective studies are necessary to establish a cause-effect relation and evaluate the preventive role of these biomarkers, aiming to improve clinical care.

FC 061OSTEOPONTIN AND ITS ASSOCIATION WITH ADVERSE EVENTS IN THE GERMAN CHRONIC KIDNEY DISEASE STUDY

Abstract Background and Aims Osteopontin (OPN) is synthesized in the thick ascending limb of Henle’s loop and in the distal tubule. Numerous studies have shown that OPN mRNA and protein expression is increased in animal models of many different renal diseases, especially glomerular diseases as well as diabetic nephropathy. Here, high OPN expression correlated with proteinuria, reduction of creatinine clearance, fibrosis as well as macrophage and T-cell infiltration. OPN has therefore been suggested to be a promising biomarker for various kidney diseases. Further studies are needed to fully understand its role in kidney (patho-)physiology and its potential as a marker of kidney disease progression and adverse renal events. We therefore evaluated the association of OPN with kidney events and all-cause mortality in a cohort of CKD patients, the German Chronic Kidney Disease (GCKD) study. Method OPN was measured from baseline serum samples using the Quantikine Human OPN Immunoassay. Coefficients of variation were <7%. Kidney events included kidney failure treated with kidney replacement therapy (dialysis, transplantation), and death due to discontinuation of dialysis treatment. Another event of interest was all-cause mortality. All events were abstracted from hospital discharge letters and death certificates by trained physicians based on a standardized endpoint catalogue. Cross-sectional regression models (dependent variables: eGFR, logUACR) adjusted for confounding variables (Table 1 legend) were fitted. Multi-variable adjusted Cox proportional hazard regression analyses were conducted. Estimated risks are expressed as cause-specific hazard ratios (HR) for all-cause mortality and kidney events, with death of other causes as the competing event. Sensitivity analyses included evaluation of all models stratified by the three most common causes of kidney disease in GCKD: hypertensive nephropathy, primary glomerular disease, and diabetic nephropathy. Results Over 6.5 years of follow-up, 473 kidney events and 582 deaths occurred among 4,950 GCKD patients. Hundred-and-forty-eight deaths and 62 kidney events occurred in 1,143 hypertensive nephropathy patients, 49 deaths and 118 kidney events occurred in 935 primary glomerular nephropathy patients, and 170 deaths and 99 kidney events in diabetic nephropathy patients (Table 1). Overall mean age was 60.1 years (±12.0), with 60.3% men. Median OPN levels were 29.2 ng/mL (IQR 21.2). Cross-sectionally a 10% change in OPN was associated with 0.5% lower eGFR on average (p<0.0001, 95% CI: -6.4 to -4.6) and a 7% change in UACR (p<0.0001, 95% CI: 0.6 to 0.8) overall. Stratified by leading cause of kidney disease, results for eGFR and UACR were of similar direction for all groups (Table 1 A). After adjusting for baseline eGFR and UACR (Table 1 B), higher OPN levels were associated with a higher risk of kidney events overall (HR 1.4, p<0.001, 95% CI 1.1-1.7). For patients with diabetic nephropathy this risk was even higher (HR 2.2, p<0.01, 95% CI 1.4-3.6). Higher OPN levels were also associated with higher risk of all-cause mortality overall (HR 1.5, p<0.0001, 95% CI 1.3-1.8) as well as for diabetic nephropathy patients (HR 1.7, p<0.01, 95% CI 1.2-2.4). HRs for the hypertensive nephropathy and primary glomerular nephropathy groups showed mostly the same effect directions, but did not reach significance after adjustment. Conclusion Higher OPN levels were associated with lower eGFR and higher UACR cross-sectionally and significantly associated with a higher risk of renal events and all-cause mortality especially for diabetic nephropathy patients even after adjustment for baseline eGFR, UACR and other confounding factors. These results are supportive of OPN being a potential marker of CKD progression and mortality.

Renal tubular arginase-2 participates in the formation of the corticomedullary urea gradient and attenuates kidney damage in ischemia-reperfusion injury in mice.

Arginase 2 (ARG2) is a mitochondrial enzyme that catalyses hydrolysis of l-arginine into urea and l-ornithine. In the kidney, ARG2 is localized to the S3 segment of the proximal tubule. It has been shown that expression and activity of this enzyme are upregulated in a variety of renal pathologies, including ischemia-reperfusion (IR) injury. However, the (patho)physiological role of ARG2 in the renal tubule remains largely unknown. We addressed this question in mice with conditional knockout of Arg2 in renal tubular cells (Arg2lox/lox /Pax8-rtTA/LC1 or, cKO mice). We demonstrate that cKO mice exhibit impaired urea concentration and osmolality gradients along the corticomedullary axis. In a model of unilateral ischemia-reperfusion injury (UIRI) with an intact contralateral kidney, ischemia followed by 24hours of reperfusion resulted in significantly more pronounced histological damage in ischemic kidneys from cKO mice compared to control and sham-operated mice. In parallel, UIRI-subjected cKO mice exhibited a broad range of renal functional abnormalities, including albuminuria and aminoaciduria. Fourteen days after UIRI, the cKO mice exhibited complex phenotype characterized by significantly lower body weight, increased plasma levels of early predictive markers of kidney disease progression (asymmetric dimethylarginine and symmetric dimethylarginine), impaired mitochondrial function in the ischemic kidney but no difference in kidney fibrosis as compared to control mice. Collectively, these results establish the role of ARG2 in the formation of corticomedullary urea and osmolality gradients and suggest that this enzyme attenuates kidney damage in ischemia-reperfusion injury.

Transcriptional trajectories of human kidney injury progression.

The molecular understanding of the progression from acute to chronic organ injury is limited. Ischemia/reperfusion injury (IRI) triggered during kidney transplantation can contribute to progressive allograft dysfunction. Protocol biopsies (n = 163) were obtained from 42 kidney allografts at 4 time points after transplantation. RNA sequencing-mediated (RNA-seq-mediated) transcriptional profiling and machine learning computational approaches were employed to analyze the molecular responses to IRI and to identify shared and divergent transcriptional trajectories associated with distinct clinical outcomes. The data were compared with the response to IRI in a mouse model of the acute to chronic kidney injury transition. In the first hours after reperfusion, all patients exhibited a similar transcriptional program under the control of immediate-early response genes. In the following months, we identified 2 main transcriptional trajectories leading to kidney recovery or to sustained injury with associated fibrosis and renal dysfunction. The molecular map generated by this computational approach highlighted early markers of kidney disease progression and delineated transcriptional programs associated with the transition to chronic injury. The characterization of a similar process in a mouse IRI model extended the relevance of our findings beyond transplantation. The integration of multiple transcriptomes from serial biopsies with advanced computational algorithms overcame the analytical hurdles related to variability between individuals and identified shared transcriptional elements of kidney disease progression in humans, which may prove as useful predictors of disease progression following kidney transplantation and kidney injury. This generally applicable approach opens the way for an unbiased analysis of human disease progression. The study was supported by the California Institute for Regenerative Medicine and by the Swiss National Science Foundation.

Podocyturia: Potential applications and current limitations.

Chronic kidney disease is a prevalent condition that affects millions of people worldwide and is a major risk factor of cardiovascular morbidity and mortality. The main diseases that lead to chronic kidney disease are frequent entities as diabetes mellitus, hypertension and glomerulopathies. One of the clinical markers of kidney disease progression is proteinuria. Moreover, the histological hallmark of kidney disease is sclerosis, located both in the glomerular and in the interstitial compartments. Glomerulosclerosis underscores an irreversible lesion that is clinically accompanied by proteinuria. In this regard, proteinuria and glomerular sclerosis are linked by the cell that has been conserved phylogenetically not only to prevent the loss of proteins in the urine, but also to maintain the health of the glomerular filtration barrier: The podocyte. It can then be concluded that the link between proteinuria, kidney disease progression and chronic kidney disease is mainly related to the podocyte. What is this situation due to? The podocyte is unable to proliferate under normal conditions, and a complex molecular machinery exists to avoid its detachment and eventual loss. When the loss of podocytes in the urine, or podocyturia, is taking place and its glomerular absolute number decreased, glomerulosclerosis is the predominant histological feature in a kidney biopsy. Therefore, tissular podocyte shortage is the cause of proteinuria and chronic kidney disease. In this regard, podocyturia has been demonstrated to precede proteinuria, showing that the clinical management of proteinuria cannot be considered an early intervention. The identification of urinary podocytes could be an additional tool to be considered by nephrologists to assess the activity of glomerulopathies, for follow-up purposes and also to unravel the pathophysiology of podocyte detachment in order to tailor the therapy of glomerular diseases more appropriately.

The glycocalyx--linking albuminuria with renal and cardiovascular disease.

Albuminuria is commonly used as a marker of kidney disease progression, but some evidence suggests that albuminuria also contributes to disease progression by inducing renal injury in specific disease conditions. Studies have confirmed that in patients with cardiovascular risk factors, such as diabetes and hypertension, endothelial damage drives progression of kidney disease and cardiovascular disease. A key mechanism that contributes to this process is the loss of the glycocalyx--a polysaccharide gel that lines the luminal endothelial surface and that normally acts as a barrier against albumin filtration. Degradation of the glycocalyx in response to endothelial activation can lead to albuminuria and subsequent renal and vascular inflammation, thus providing a pathophysiological framework for the clinical association of albuminuria with renal and cardiovascular disease progression. In this Review, we examine the likely mechanisms by which glycocalyx dysfunction contributes to kidney injury and explains the link between cardiovascular disease and albuminuria. Evidence suggests that glycocalyx dysfunction is reversible, suggesting that these mechanisms could be considered as therapeutic targets to prevent the progression of renal and cardiovascular disease. This possibility enables the use of existing drugs in new ways, provides an opportunity to develop novel therapies, and indicates that albuminuria should be reconsidered as an end point in clinical trials.

Pathogenesis of common glomerular diseases – role of the podocyte cytoskeleton

Pathogenesis of common glomerular diseases – role of the podocyte cytoskeleton Takanori Kumagai, Flaviana Mouawad, Tomoko TakanoDepartment of Medicine, McGill University Health Centre, Montreal, Quebec, CanadaAbstract: Glomerulus is the filtration unit of the kidney where the first step of urine formation takes place. In the glomerulus, water and small molecules including waste products of the body are filtered into the urine, while large molecules essential for body function such as albumin are retained. When this barrier function of the kidney is impaired, protein leakage into the urine (proteinuria) occurs. Proteinuria is not only a hallmark of many glomerular diseases but also a prognostic marker of kidney disease progression. Visceral glomerular epithelial cells (commonly called podocytes) are known to have an important role in the maintenance of glomerular barrier function. In the last decade, remarkable progress has been made in podocyte biology, mainly led by the discoveries of important proteins that work together to maintain the intricate morphology and function of podocytes. Most of these so-called podocyte proteins modulate the actin cytoskeleton either directly or indirectly. The aim of the current review is to discuss the pathogenesis of common glomerular diseases with a particular focus on the role of the actin cytoskeleton in podocytes. The diseases covered include minimal change disease, focal segmental glomerulosclerosis (idiopathic and hereditary), membranous nephropathy, hypertensive glomerulosclerosis, and diabetic nephropathy.Keywords: glomerular disease, podocyte, cytoskeleton, proteinuria

Hematopoietic growth factor inducible neurokinin-1 (Gpnmb/Osteoactivin) is a biomarker of progressive renal injury across species

We sought to find a urinary biomarker for chronic kidney disease and tested hematopoietic growth factor inducible neurokinin-1 (HGFIN, also known as Gpnmb/Osteoactivin) as it was found to be a kidney injury biomarker in microarray studies. Here, we studied whether HGFIN is a marker of kidney disease progression. Its increase in kidney disease was confirmed by real-time PCR after 5/6 nephrectomy, in streptozotocin-induced diabetes, and in patients with chronic kidney disease. In the remnant kidney, HGFIN mRNA increased over time reflecting lesion chronicity. HGFIN was identified in the infarct portion of the remnant kidney in infiltrating hematopoietic interstitial cells, and in distal nephron tubules of the viable remnant kidney expressed de novo with increasing time. In vitro, it localized to cytoplasmic vesicles and cell membranes. Epithelial cells lining distal tubules and sloughed luminal tubule cells of patients expressed HGFIN protein. The urine HGFIN-to-creatinine ratio increased over time after 5/6 nephrectomy; increased in patients with proteinuric and polycystic kidney disease; and remained detectable in urine after prolonged freezer storage. The urine HGFIN-to-creatinine ratio compared favorably with the urine neutrophil gelatinase-associated lipocalin (NGAL)-to-creatinine ratio (both measured by commercial enzyme-linked immunosorbent assays (ELISAs)), and correlated strongly with proteinuria, but weakly with estimated glomerular filtration rate and serum creatinine. Thus, HGFIN may be a biomarker of progressive kidney disease.

Effect of blood pressure lowering on markers of kidney disease progression

Hypertension remains a common comorbidity and cause of chronic kidney disease (CKD). As the number of patients with CKD grows, so does the need to identify modifiable risk factors for CKD progression. Data on slowing progression of CKD or preventing end-stage renal disease with aggressive blood pressure control have not yielded definitive conclusions regarding ideal blood pressure targets. Shifting the focus of antihypertensive therapy to alternative markers of end-organ damage, specifically proteinuria, has yielded some promise in preventing the progression of CKD. Nevertheless, proteinuria and decline in estimated GFR may represent an irreversible degree of injury to the kidney that limits the impact of any therapy. The identification and use of novel markers of kidney injury to assess the impact of antihyper-tensive therapy may yield clearer direction with regard to optimal management of hypertension in the setting of CKD.

Hypertension diagnosis and prognosis in chronic kidney disease with out-of-office blood pressure monitoring

Hypertension is an important risk factor for adverse cardiovascular and renal outcomes particularly in patients with chronic kidney disease. This review compares blood pressure measurements obtained in the clinic with those obtained outside the clinic to predict cardiovascular and renal injury and outcomes. When home blood pressure monitoring (self-measured blood pressure) is performed, hypertension is less frequently misclassified and better correlation is achieved with putative markers of kidney disease progression. Masked hypertension - normotension in the clinic, hypertension at home - is associated with higher risk of end-stage renal disease in patients with chronic kidney disease. Conversely, 'white coat' hypertension - hypertension in the clinic and normotension at home - is associated with better renal outcomes. Ambulatory blood pressure monitoring is also prognostically superior to clinic blood pressure but does not further refine the prognosis made by home blood pressure monitoring. In patients on hemodialysis, home blood pressure, not predialysis and postdialysis blood pressure, shares the combination of high sensitivity and high specificity of greater than 80% to make a diagnosis of hypertension with the reference standard of ambulatory blood pressure monitoring. In addition, home blood pressure is a better correlate of left ventricular hypertrophy in patients on hemodialysis compared with peridialysis blood pressure. Home blood pressure monitoring should be an essential part of management of hypertension in patients with all stages of chronic kidney disease.