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Proenkephalin (PENK) as a Novel Biomarker for Kidney Function
Abstract
Background
The assessment of kidney function and detection of acute kidney injury (AKI) remain cumbersome. On the one hand, because of limited accuracy of established tests: The most widely used methods are creatinine based, which lack in sensitivity, as creatinine is not purely filtrated by the kidney and rises relatively late after onset of AKI. On the other hand, because of labor-intensiveness: Gold standard inulin clearance and comparable methods involve intravenous compound infusion, blood sampling at several time points, and have error-sensitive determination methods. In recent years, several biomarkers have been put forward (e.g., NGAL, KIM-1, TIMP-2*IGFBP-7), but clinical implementation is limited up to now.
Content
Proenkephalin (PENK) represents a new candidate to determine kidney function. This peptide is cleaved from the precursor peptide preproenkephalin A alongside enkephalins (endogenous opioids) and is filtrated in the glomerulus. PENK plasma concentration appears to accurately represent glomerular filtration rate in patients diagnosed with sepsis or cardiac diseases. Moreover, increased PENK concentration is found to be associated with longer-term outcome concerning AKI and cardiac diseases. Lastly, the predominant receptor of enkephalins, the δ-opioid receptor, is expressed with the highest density in the kidney, suggesting that enkephalins could also exert a direct effect on kidney function.
Summary
In this review, we present an overview of enkephalins and the assessment of kidney function using this possible new functional biomarker PENK and compare it with established and novel biomarkers.
... Enkephalins are endogenous opioid peptides that exert cardiodepressive effects, such as reducing heart rate and inhibiting norepinephrine release, as well as improving renal function by increasing renal blood flow and urinary output. [1][2][3][4][5] Proenkephalin (PENK) is a stable surrogate for enkephalins. 3 In subjects from the general population, higher concentrations of PENK were associated with a higher risk of development of chronic kidney disease (CKD). ...
... The association between PENK concentrations and renal dysfunction might be explained by compensatory increased PENK production to exert kidney protective effects, 2 or alternatively reflect impaired clearance since PENK is likely to be freely filtered through the glomerulus due to its low molecular weight (4586.60 g/mol) and is not known to have a binding protein. 5 PENK has therefore also been suggested as a reflector of glomerular function especially in the acute setting. 5,28 Whatever the underlying mechanisms are, PENK concentrations have previously been associated with decline of eGFR and incident CKD in the general population, 6 although in a previous study conducted in PREVEND this association was only found in men. ...
... 5 PENK has therefore also been suggested as a reflector of glomerular function especially in the acute setting. 5,28 Whatever the underlying mechanisms are, PENK concentrations have previously been associated with decline of eGFR and incident CKD in the general population, 6 although in a previous study conducted in PREVEND this association was only found in men. 7 The heart and the kidney are closely intertwined where failure of one can lead to failure of the other, 29 7 We also found that higher PENK concentrations were associated with higher NT-proBNP concentrations. ...
Background
Enkephalins of the opioid system exert several cardiorenal effects. Proenkephalin (PENK), a stable surrogate, is associated with heart failure (HF) development after myocardial infarction and worse cardiorenal function and prognosis in patients with HF. The association between plasma PENK concentrations and new-onset HF in the general population remains to be established.
Hypothesis
We hypothesized that plasma PENK concentrations are associated with new-onset HF in the general population.
Methods
We included 6677 participants from the prevention of renal and vascular end-stage disease study and investigated determinants of PENK concentrations and their association with new-onset HF (both reduced [HFrEF] and preserved ejection fraction [HFpEF]).
Results
Median PENK concentrations were 52.7 (45.1–61.9) pmol/L. Higher PENK concentrations were associated with poorer renal function and higher NT-proBNP concentrations. The main determinants of higher PENK concentrations were lower estimated glomerular filtration rate (eGFR), lower urinary creatinine excretion, and lower body mass index (all p < .001). After a median 8.3 (7.8–8.8) years follow-up, 221 participants developed HF; 127 HFrEF and 94 HFpEF. PENK concentrations were higher in subjects who developed HF compared with those who did not, 56.2 (45.2–67.6) versus 52.7 (45.1–61.6) pmol/L, respectively (p = .003). In competing-risk analyses, higher PENK concentrations were associated with higher risk of new-onset HF (hazard ratio [HR] = 2.09[1.47–2.97], p < .001), including both HFrEF (HR = 2.31[1.48–3.61], p < .001) and HFpEF (HR = 1.74[1.02–2.96], p = .042). These associations were, however, lost after adjustment for eGFR.
Conclusions
In the general population, higher PENK concentrations were associated with lower eGFR and higher NT-proBNP concentrations. Higher PENK concentrations were not independently associated with new-onset HFrEF and HFpEF and mainly confounded by eGFR.
... The glomeruli freely filter proenkephalin A due to its small molecular size (4.5 kDa); it has no known tubular handling or extrarenal clearance. It is not bound to plasma proteins and is stably produced in various disease states independent of inflammation and other non-renal factors [49]. Therefore, proenkephalin A is considered a marker of kidney function. ...
... Therefore, proenkephalin A is considered a marker of kidney function. Its plasma concentrations have been strongly negatively correlated with measured GFR [49,103]. A study of 24 septic patients in the ICU reported that proenkephalin A concentration levels were highly correlated with measured GFR calculated with iohexol (r 2 = 0.91; p < 0.001) [104]. ...
Recent advances have improved our understanding of the epidemiology and pathophysiology of acute kidney injury (AKI). So far, the Kidney Disease: Improving Global Outcome guidelines define and stratify kidney injury based on increases in serum creatinine level and/or decreases in urine output. Although the term AKI acknowledges the existence of cellular injury, its diagnosis is still only defined by the reduced excretory function of the kidney. New biomarkers that aid a better understanding of the relationship between acute tubular injury and kidney dysfunction have been identified, reflecting the advances in molecular biology. The expression of some of these novel biomarkers precedes changes in conventional biomarkers or can increase their predictive power. Therefore, they might enhance the clinical accuracy of the definition of AKI. This review summarizes the limitations of the current AKI classification and a panel of candidate biomarkers for augmenting AKI classification and recognition of AKI subphenotypes. We expect that the integration of appropriately selected biomarkers in routine clinical practice can improve AKI care.
... Proenkephalin A and opioid receptors are widely produced in the body and are particularly abundant in the kidney (10 ). Proenkephalin is a functional kidney marker closely correlated with the true GFR (11 ). Previous single-center clinical studies with small numbers of patients, characterized by low severity, have shown that increased plasma penKid can predict AKI in patients with sepsis (12,13 ). ...
... They also predict a progressive decline in eGFR and incident chronic kidney disease in the general population (22 ), functional decline in stable renal transplant recipients (23 ), or AKI after cardiac surgery (24,25 ). All these data therefore point to penKid as a functional renal marker, strongly correlated with the true GFR, as determined by iohexol clearance in septic patients with and without kidney dysfunction (11 ). ...
Background:
Acute kidney injury (AKI)9 occurs in many critically ill patients and is associated with high mortality. We examined whether proenkephalin could predict incident AKI and its improvement in septic patients.
Methods:
Plasma proenkephalin A 119-159 (penKid) was assayed in 956 patients with sepsis or septic shock enrolled in the multicenter Albumin Italian Outcome Sepsis (ALBIOS) trial to test its association with incident AKI, improvement of renal function, need for renal replacement therapy (RRT), and mortality.
Results:
Median [Q1-Q3] plasma penKid concentration on day 1 [84 (20-159) pmol/L[ was correlated with serum creatinine concentration (r = 0.74); it was higher in patients with chronic renal failure and rose progressively with the renal Sequential Organ Failure Assessment subscore. It predicted incident AKI within 48 h (adjusted odds ratio, 3.3; 95% CI, 2.1-5.1; P < 0.0001) or 1 week [adjusted hazard ratio, 2.1 (1.7-2.8); P < 0.0001] and future RRT during the intensive care unit stay [odds ratio, 4.0 (3.0-5.4)]. PenKid was also associated with improvements in renal function in patients with baseline serum creatinine >2 mg/dL, both within the next 48 h [adjusted odds ratio, 0.31 (0.18-0.54), P < 0.0001] and 1 week [0.23 (0.12-0.45)]. The time course of penKid concentrations predicted AKI and 90-day mortality.
Conclusions:
Early measurement and the trajectory of penKid predict incident AKI, improvement of renal function, and the need for RRT in the acute phase after intensive care unit admission during sepsis or septic shock. PenKid measurement may be a valuable tool to test early therapies aimed at preventing the risk of AKI in sepsis.
... Since the density of opioid receptors is highest in the kidneys, enkephalins are implicated in kidney function regulation [19]. PENK possesses several characteristics for an ideal GFR biomarker: it is endogenous, freely filtered by glomeruli due to its small molecular size (4.5 kDa), has no known tubular handling or extra-renal clearance, is not bound to plasma proteins and is stably produced in various disease states, independent of inflammation and other non-renal factors [20]. ...
... Research in healthy and diseased adults supports PENK as an early indicator of AKI and independent predictor of impaired kidney function. Moreover, PENK was strongly correlated with estimated and measured GFR after cardiac surgery and in septic patients [20][21][22][23][24][25][26][27][28][29]. ...
Objectives
Acute kidney injury (AKI) is common in critically ill children, but current biomarkers are suboptimal. Proenkephalin A 119–159 (PENK) is a promising new biomarker for AKI in adults, but pediatric data is lacking. We determined PENK reference intervals for healthy children, crucial for clinical implementation, and explored concentrations in critically ill infants aged under 1 year.
Methods
Observational cohort study in healthy infants and critically ill children aged 0–1 years. Reference values were determined using generalized additive models. Plasma PENK concentrations between healthy children and critically ill children with and without AKI, were compared using linear mixed modelling. The performance of PENK as AKI biomarker was compared to cystatin C (CysC) and β-trace protein (BTP) using receiver-operating-characteristic (ROC) analysis.
Results
PENK concentrations in 100 healthy infants were stable during the first year of life (median 517.3 pmol/L). Median PENK concentrations in 91 critically ill children, were significantly higher in those with AKI (n=40) (KDIGO Stage 1 507.9 pmol/L, Stage 2 704.0 pmol/L, Stage 3 930.5 pmol/L) than non-AKI patients (n=51, 432.2 pmol/L) (p < 0.001). PENK appeared to relate better to AKI diagnosis than CysC and BTP (AUROC PENK 0.858, CysC 0.770 and BTP 0.711) in the first 24 h after recruitment.
Conclusions
PENK reference values are much higher in young infants than adults, but clearly discriminate between children with and without AKI, with comparable or better performance than CysC and BTP. Our results illustrate the importance of establishing age-normalized reference values and indicate PENK as a promising pediatric AKI biomarker.
... PENK is a small endogenous opioid peptide, which is cleaved from the common endogenous opioid precursor, and thus can be used as a surrogate marker for the activity of the endogenous opioid system [8]. The opioid system has been shown to have depressive effects on cardiac and renal function, and has been implicated in the prognosis of myocardial infarction [9]. ...
Background
Acute kidney injury (AKI) is a frequent form of organ injury in cardiogenic shock. However, data on AKI markers such as plasma proenkephalin (P-PENK) and neutrophil gelatinase-associated lipocalin (P-NGAL) in cardiogenic shock populations are lacking. The objective of this study was to assess the ability of P-PENK and P-NGAL to predict acute kidney injury and mortality in cardiogenic shock.
Results
P-PENK and P-NGAL were measured at different time points between baseline and 48 h in 154 patients from the prospective CardShock study. The outcomes assessed were AKI defined by an increase in creatinine within 48 h and all-cause 90-day mortality. Mean age was 66 years and 26% were women. Baseline levels of P-PENK and P-NGAL (median [interquartile range]) were 99 (71–150) pmol/mL and 138 (84–214) ng/mL. P-PENK > 84.8 pmol/mL and P-NGAL > 104 ng/mL at baseline were identified as optimal cut-offs for AKI prediction and independently associated with AKI (adjusted HRs 2.2 [95% CI 1.1–4.4, p = 0.03] and 2.8 [95% CI 1.2–6.5, p = 0.01], respectively). P-PENK and P-NGAL levels at baseline were also associated with 90-day mortality. For patients with oliguria < 0.5 mL/kg/h for > 6 h before study enrollment, 90-day mortality differed significantly between patients with low and high P-PENK/P-NGAL at baseline (5% vs. 68%, p < 0.001). However, the biomarkers provided best discrimination for mortality when measured at 24 h. Identified cut-offs of P-PENK 24h > 105.7 pmol/L and P-NGAL 24h > 151 ng/mL had unadjusted hazard ratios of 5.6 (95% CI 3.1–10.7, p < 0.001) and 5.2 (95% CI 2.8–9.8, p < 0.001) for 90-day mortality. The association remained significant despite adjustments with AKI and two risk scores for mortality in cardiogenic shock.
Conclusions
High levels of P-PENK and P-NGAL at baseline were independently associated with AKI in cardiogenic shock patients. Furthermore, oliguria before study inclusion was associated with worse outcomes only if combined with high baseline levels of P-PENK or P-NGAL. High levels of both P-PENK and P-NGAL at 24 h were found to be strong and independent predictors of 90-day mortality.
Trial registration : NCT01374867 at www.clinicaltrials.gov , registered 16 Jun 2011—retrospectively registered
... Proenkephalin A 119-159 (penKid) is a 5 kDa peptide derived from the same precursor as met-and leu-Enkephalins and is considered a stable surrogate marker for the unstable enkephalins. [9] While numerous functions of enkephalins have been described, including stimulation of kidney function, [10] penKid might be a "connecting peptide" in the precursor only, presumably without a function in the blood circulation. There is no evidence for penKid being possibly protein-bound, as linearity and recovery in the penKid assay have been found to be not impaired. ...
Introduction
Sepsis is the leading cause of acute kidney injury (AKI) in critically ill patients. The Kidney in Sepsis and Septic Shock (Kid-SSS) study evaluated the value of proenkephalin A 119-159 (penkid)—a sensitive biomarker of glomerular function, drawn within 24 hours upon intensive care unit (ICU) admission and analyzed using a chemiluminescence immunoassay—for kidney events in sepsis and septic shock.
Methods
The Kid-SSS study was a substudy of Adrenomedullin and Outcome in Severe Sepsis and Septic Shock (AdrenOSS) (NCT02393781), a prospective, observational, multinational study including 583 patients admitted to the intensive care unit with sepsis or septic shock and a validation cohort of 525 patients from the French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study. The primary endpoint was major adverse kidney events (MAKEs) at day 7, composite of death, renal replacement therapy, and persistent renal dysfunction. The secondary endpoints included AKI, transient AKI, worsening renal function (WRF), and 28-day mortality.
Results
Median age was 66 years (interquartile range 55–75), and 28-day mortality was 22% (95% confidence interval [CI] 19%−25%). Of the patients, 293 (50.3%) were in shock upon ICU admission. Penkid was significantly elevated in patients with MAKEs, persistent AKI, and WRF (median = 65 [IQR = 45–106] vs. 179 [114–242]; 53 [39–70] vs. 133 [79–196] pmol/l; and 70 [47–121] vs. 174 [93–242] pmol/l, all P < 0.0001), also after adjustment for confounding factors (adjusted odds ratio = 3.3 [95% CI = 1.8–6.0], 3.9 [95% CI = 2.1–7.2], and 3.4 [95% CI = 1.9–6.2], all P < 0.0001). Penkid increase preceded elevation of serum creatinine with WRF and was low in renal recovery.
Conclusion
Admission penkid concentration was associated with MAKEs, AKI, and WRF in a timely manner in septic patients.
... PENK appears to be freely filtrated in the glomerulus, and it is indeed the case that, with declining eGFR, PENK levels rise. The association between PENK and renal function could thus be explained by PENK being a filtration signal, for which interest has already previously been shown to use PENK as an easy and reliable determinant of current GFR and possibly a better early indicator of kidney function decline and kidney injury, 34 but PENK might also serve a functional purpose. ...
Background:
PENK (proenkephalin) is a stable surrogate for enkephalins, endogenous opioid peptides, which exert cardiodepressive effects and improve renal function. PENK has been associated with heart failure (HF) severity and renal dysfunction. We therefore hypothesized that PENK could be associated with deterioration of kidney function and could have a role as a novel renal marker in HF.
Methods and results:
In 2180 patients with HF of a large multicenter cohort (BIOSTAT-CHF [A Systems Biology Study to Tailored Treatment in Chronic Heart Failure]), the relationship between PENK and clinical variables, plasma and urinary biomarkers, and clinical end points was established. Data were validated in a separate cohort of 1703 patients with HF. PENK was elevated (>80 pmol/L, 99th percentile) in 1245 (57%) patients. Higher PENK was associated with more advanced HF and glomerular and tubular dysfunction. The strongest independent predictor of PENK was estimated glomerular filtration rate. Others were plasma NGAL (neutrophil gelatinase-associated lipocalin) and NT-proBNP (N-terminal pro-B-type natriuretic peptide; all P<0.001). Using correlation heatmaps and hierarchical cluster analyses, PENK clustered with estimated glomerular filtration rate, creatinine, NGAL, galectin-3, and urea. Higher PENK was independently associated with increased risk of deterioration of kidney function between baseline and 9 months (odds ratio, 1.29 [1.02-1.65] per PENK doubling; P=0.038; defined as >25% decrease in estimated glomerular filtration rate) and mortality (hazard ratio, 1.23 [1.07-1.43] per doubling; P=0.004). Analyses in the validation cohort yielded comparable findings.
Conclusions:
Higher PENK levels are associated with more severe HF, with glomerular and tubular renal dysfunction, with incidence of a deterioration of kidney function, and with mortality. These findings suggest that the opioid system might be involved in deteriorating kidney function in HF.
... In this setting, RFR with oral protein load can be a useful tool to discriminate patients more prone to evolve to CKD/ESRD. Moreover, RFR could be integrated with new biomarkers of renal function (proenkephalin, cystatin-C, or direct measure of renal function) (3,12) and nephron mass (e.g., uromodulin) (16) able to improve the identification of CKD progression. ...
Coronavirus disease 2019 (COVID-19) poses an unprecedented challenge to world health systems substantially increasing hospitalization and mortality rates in all affected countries. Being primarily a respiratory disease, COVID-19 is mainly associated with pneumonia or minor upper respiratory tract symptoms; however, different organs can sustain considerable (if not terminal) damage because of coronavirus. Acute kidney injury (AKI) is the most common complication of COVID-19-related pneumonia and more than 20% of patients requiring ventilatory support develop renal failure. Additionally, chronic kidney disease (CKD) is a major risk factor for COVID-19 severity and mortality. All these data demonstrate the relevance of renal function assessment in COVID-19 patients and the need of early kidney-directed diagnostic and therapeutic approaches. However, the sole assessment of renal function could be not entirely indicative of kidney tissue status. In this viewpoint, we argument about the clinical significance and the potential relevance of renal functional reserve evaluation in COVID-19 patients.
... 38 Although the mechanism of enkephalin in regulating renal function is unclear, it was proposed to involve neurohormonal activation under stress and inflammation. 39 Due to its low molecular weight, penkid is filtered freely through the glomerulus. 40 Hence, it has been further investigated as a novel filtration marker. ...
Biomarkers have become a pillar of precision medicine in acute kidney injury (AKI). Traditional markers for diagnosis of AKI are insensitive and insufficient to provide comprehensive information for prognostication. Several emerging biomarkers have shown promising results in large-scale clinical studies. These novel markers likely will be beneficial for personalized AKI prevention and treatment.
... Proenkefalin (PENK) is an endogenous opioid polypeptide hormone expressed in many tissues, including the kidney (122). It is a biomarker that shows kidney function (not damage) closely related to GFR (123,124). It is a predictor of the development of AKI because it increases before SCr (125). ...
Acute kidney injury (AKI) is a common public health problem and has a significant impact on cardiovascular disease, mortality and increased hospital costs. Also, AKI can progress to chronic kidney disease (CKD). Therefore, early diagnosis is very important for AKI. Serum creatinine (SCr) is a well-known biomarker in the diagnosis of AKI. However, changes in SCr levels are insufficient in early diagnosis so, new biomarkers are needed. Because of that, the search for biomarkers for the early detection of AKI is an ongoing process. In recent years, early diagnosis, prognostic and predictive biomarkers have been discovered to replace or support SCr in the diagnosis of AKI. New biomarkers can help early diagnosis and effective management of AKI. Since there are many biomarkers, when and under which condition these biomarkers should be used cause confusion. In this review, we aimed to construct and ease to use classification of these AKI biomarkers and summarize the current literature. We have divided the biomarkers into two main categories: renal and non-renal origin. Then, we have classified the biomarkers of renal origin as glomerular, tubular and unknown renal site. We have also described the clinical use of these biomarkers for diagnosis and prognosis.
... [PENK]), before and after UER events, is also warranted [156,217,218]. ...
It is well established that physical activity reduces all-cause mortality and can prolong life. Ultra-endurance running (UER) is an extreme sport that is becoming increasingly popular, and comprises running races above marathon distance, exceeding 6-hours, and/or running fixed distances on multiple days. Serious acute adverse events are rare but there is mounting evidence that UER may lead to long-term health problems. The purpose of this review is to present the current state of knowledge regarding the potential long-term health problems derived from UER, specifically potential maladaptation in key organ systems including cardiovascular, respiratory, musculoskeletal, renal, immunological, gastrointestinal, neurological, and integumentary systems. Special consideration is given to youth, masters, and female athletes, all of whom may be more susceptible to certain long-term health issues. We present directions for future research into the pathophysiological mechanisms that underpin athlete susceptibility to long-term issues. Although all body systems can be affected by UER, one of the clearest effects of endurance exercise is on the cardiovascular system, including right ventricular dysfunction and potential increased risk of arrhythmias and hypertension. There is also evidence that rare cases of acute renal injury in UER could lead to progressive renal scarring and chronic kidney disease. There are limited data specific to female athletes who may be at greater risk of certain UER-related health issues due to interactions between energy availability and sex-hormone concentrations. Indeed, failure to consider sex differences in the design of female specific UER training programs may have a negative impact on athlete longevity. It is hoped that this review will inform risk stratification and stimulate further research about UER and the implications for long-term health.
L’insuffisance rénale aigue (IRA), définie comme une altération brutale de la fonction de filtration rénale, est un véritable problème de santé publique par sa fréquence et son importante morbi-mortalité. La physiopathologie de ce syndrome est encore incomplètement comprise mais elle implique une adaptation métabolique insuffisante de l’épithélium tubulaire rénal dont les mécanismes régulateurs ne sont pas complètement connus. Ce déficit d’adaptation est à l’origine d’une souffrance cellulaire expliquant en partie les lésions tissulaires. De plus, ce syndrome est souvent ignoré ou identifié trop tardivement, en raison de critères diagnostiques imparfaits. Ces lacunes expliquent qu’il n’existe à l’heure actuelle aucun traitement spécifique efficace. Mon travail de thèse s’est organisé autour de ces trois problématiques : physiopathologique, thérapeutique et diagnostique.Le premier axe de mon travail, physiopathologique, a évalué le rôle du facteur de transcription Hepatocyte Nuclear Factor 1 β (HNF-1β) dans la régulation du métabolisme, notamment énergétique, au sein de l’épithélium tubulaire rénal. Nous avons démontré que l’invalidation de ce facteur de transcription dans une lignée tubulaire proximale murine, induit une réorientation du métabolisme énergétique en conditions basales, avec réduction du métabolisme oxydatif mitochondrial et augmentation de la glycolyse, sans d’autre explication que la modulation de PGC-1α. Ces anomalies, proches de celles induites par l’hypoxie dans les cellules sauvages, ne permettent pas d’adaptation supplémentaire des cellules invalidées à un stress. L’invalidation d’Hnf1b induit également des modifications métaboliques au-delà de la production énergétique à l’image de la synthèse des phospholipides, potentiellement en lien avec un régulation directe de la choline kinase-α. Ce travail confirme un rôle d’Hnf1b dans le métabolisme cellulaire énergétique, pouvant expliquer une partie du phénotype des patients souffrant d’une mutation de ce facteur mais le plaçant aussi comme un régulateur de la réponse à l’agression en situation générale Le deuxième axe, thérapeutique, s’est intéressé aux anomalies de la voie de biosynthèse de novo du Nicotinamide Adénine Dinucléotide (NAD) à partir du tryptophane en contexte d’IRA. En comparant, par approche métabolomique ciblée, la composition des urines de patients développant ou non une IRA, après chirurgie cardiaque, nous avons pu confirmer dans un nombre plus important de patients, certaines anomalies observés dans des études antérieures. Néanmoins, à l’inverse d’observations publiées, une supplémentation en nicotinamide, précurseur alternatif de la biosynthèse du NAD, ne permet pas de restaurer le stock intra-rénal de NAD ni d’améliorer les conséquences rénales d’une ischémie-reperfusion chez la souris. Ces résultats incitent à la prudence quant à l’efficacité attendue de ce traitement, en cours d’essai thérapeutique. Le troisième axe, diagnostique, s’est intéressé à l’identification de biomarqueurs urinaires permettant le diagnostic d’une IRA. Nous avons identifié, par approche peptidomique sur des urines prélevées précocement après chirurgie cardiaque, de nombreux peptides différentiellement présents en cas d’IRA. Leur combinaison en une signature permet un diagnostic précoce de l’AKI avec de bonnes performances (AUC = 0.79) dans divers contextes. La poursuite de ces analyses, avec utilisation de nouvelles approches (métabolomique) ou de combinaisons d’approches (multiomics, scores clinico-biologiques), donnent déjà de bons résultats accroissant encore ce bénéfice diagnostique avec même un potentiel prédictif. Bien que préliminaire et difficilement transposable en l’état à la pratique, ce type d’approche offre des perspectives intéressantes dans le diagnostic et la prédiction de cette affection. Ce travail de thèse, a permis de mettre en évidence de nouveaux éléments utiles concernant la physiopathologie, le traitement et le diagnostic de l’IRA.
Acute kidney injury (AKI) is a common and serious complication in hospitalized patients, which continues to pose a clinical challenge for treating physicians. The most recent Kidney Disease Improving Global Outcomes practice guidelines for AKI have restated the importance of earliest possible detection of AKI and adjusting treatment accordingly. Since the emergence of initial studies examining the use of neutrophil gelatinase-associated lipocalin (NGAL) and cycle arrest biomarkers, tissue inhibitor metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein (IGFBP7), for early diagnosis of AKI, a vast number of studies have investigated the accuracy and additional clinical benefits of these biomarkers. As proposed by the Acute Dialysis Quality Initiative, new AKI diagnostic criteria should equally utilize glomerular function and tubular injury markers for AKI diagnosis. In addition to refining our capabilities in kidney risk prediction with kidney injury biomarkers, structural disorder phenotypes referred to as "preclinical-" and "subclinical AKI" have been described and are increasingly recognized. Additionally, positive biomarker test findings were found to provide prognostic information regardless of an acute decline in renal function (positive serum creatinine criteria). We summarize and discuss the recent findings focusing on two of the most promising and clinically available kidney injury biomarkers, NGAL and cell cycle arrest markers, in the context of AKI phenotypes. Finally, we draw conclusions regarding the clinical implications for kidney risk prediction.
This research attempted to elucidate the molecular components are involved in the pathogenesis of recurrent implantation failure (RIF). We initially identified that 386 mRNAs, 144 miRNAs and 2548 circRNAs were differentially expressed (DE) in RIF and then investigated the genetic cause of the observed abnormal expression by constructing a circRNA-miRNA-mRNA network considering the competing endogenous RNA theory. We further analysed the upstream transcription factors and related kinases of DEmRNAs (DEMs) and demonstrated that SUZ12, AR, TP63, NANOG, and TCF3 were the top five TFs binding to these DEMs. Besides, protein-protein interaction analysis disclosed that ACTB, CXCL10, PTGS2, CXCL12, GNG4, AGT, CXCL11, SST, PENK, and FOXM1 were the top 10 hub genes in the acquired network. Finally, we performed the functional enrichment analysis and found that arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), pathways in cancer, TNF signalling pathway and steroid hormone biosynthesis were the potentially disrupted pathways in RIF patients. Optimistically, our findings may deepen our apprehensions about the underlying molecular and biological causes of RIF and provide vital clues for future laboratory and clinical experiments that will ultimately bring a better outcome for patients with RIF.
Biomarkers are increasingly used in patients with serious infections in the critical care setting to complement clinical judgment and interpretation of other diagnostic and prognostic tests. The main purposes of such blood markers are (1) to improve infection diagnosis (i.e., differentiation between bacterial vs. viral vs. fungal vs. noninfectious), (2) to help in the early risk stratification and thus provide prognostic information regarding the risk for mortality and other adverse outcomes, and (3) to optimize antibiotic tailoring to individual needs of patients (“antibiotic stewardship”).
Especially in critically ill patients, in whom sepsis is a major cause of morbidity and mortality, rapid diagnosis is desirable to start timely and specific treatment.
Besides some biomarkers, such as procalcitonin, which is well established and has shown positive effects in regard to utilization of antimicrobials and clinical outcomes, there is a growing number of novel markers from different pathophysiological pathways, where the final proof of an added value to clinical judgment and ultimately clinical benefit to patients is still lacking.
Without a doubt, the addition of blood biomarkers to clinical medicine has had a strong impact on the way we care for patients today. Recent trials show that as an adjunct to other clinical and laboratory parameters these markers provide important information about risks for bacterial infection and resolution of infection. Moreover, biomarkers can help to optimize management of patients with serious illness in the intensive care unit, thereby offering more individualized treatment courses with overall improvements in clinical outcomes.
Objectives
The opioid neuropeptide pro-enkephalin A (PENK-A) may be a circulating marker of cardiovascular risk, with prior findings relevant to heart failure, kidney disease, and vascular dementia. Despite these findings, the association of PENK-A with ischemic stroke is unknown, so we examined this association in a prospective cohort study and analyzed differences by race and sex.
Materials and Methods
The REasons for Geographic and Racial Differences in Stroke study (REGARDS) is a prospective cohort study of 30,239 Black and White adults. Plasma PENK-A was measured in 473 participants that developed first-time ischemic stroke over 5.9 years and 899 randomly selected participants. Cox models adjusted for demographics and stroke risk factors were used to calculate hazard ratios (HRs) of stroke by baseline PENK-A.
Results
PENK-A was higher with increasing age, female sex, White race, lower body mass index, and antihypertensive medication use. Each SD higher increment of PENK-A was associated with an adjusted HR of 1.20 (95% CI 1.01-1.42) for stroke, with minimal confounding by stroke risk factors. Spline plots suggested a U-shaped relationship, particularly in White men, with an adjusted HR 3.88 (95% CI 1.94-7.77) for the 95th versus 50th percentile of PENK-A in White men.
Conclusions
Higher baseline plasma PENK-A was independently associated with future stroke risk in REGARDS. This association was most apparent among White men. There was little confounding by established stroke risk factors, suggesting a possible causal role in stroke etiology. Further research is needed to understand the role of endogenous opioids in stroke pathogenesis.
Acute kidney injury (AKI) describes a heterogeneous group of conditions, without specification of their etiology and diagnosed only by indirect markers of glomerular filtration rate (GFR), such as serum creatinine and urine output. Bedside estimation of GFR and detection of structural alterations with novel biomarkers, and stress tests have more recently been developed. These novel findings should probably be included in future AKI definitions. Chronic kidney disease (CKD) is defined by abnormalities in kidney function and structure that persist over >3 months and is classified according to cause, GFR, and albuminuria. Acute kidney disease (AKD) is the term representing patients with abnormalities of function and structure with a duration of ≤3 months that fall outside the definitions of AKI or CKD. Since AKI is by definition also AKD, 2 types of AKD have been proposed, one with and one without AKI. AKD without AKI is common, often undetected, occurs frequently in the outpatient population and shows increased risk of CKD, ESKD and mortality. Alternatively, AKD has also been defined as the period of incomplete recovery following an AKI episode, the latter limited for the duration of 7 days. This contribution discusses the pros and cons of the existence of these 2 definitions of AKD.
Background:
Endogenous opioids, enkephalins, are known to increase with acute kidney injury. Since the mature pentapeptides are unstable, we evaluated the performance of an assay that measures proenkephalin 119-159 (PENK), a stable peptide formed concomitantly with mature enkephalins.
Methods:
PENK assay performance was evaluated on two microtiterplate/chemiluminescence sandwich immunoassay formats that required 18 or 1 h incubation times. PENK concentration was measured in plasma from healthy individuals to establish a reference interval and in patients with varied levels of kidney function and comorbidities to assess the association with measured glomerular filtration rate (mGFR) using iothalamate clearance.
Results:
Assay performance characteristics in plasma were similar between the assay formats. Limit of quantitation was 26.0 pmol/L (CV = 20%) for the 1 h assay and 17.3 pmol/L (CV = 3%) for the 18 h assay. Measurable ranges were 26-1540 pmol/L (1 h assay) and 18-2300 pmol/L (18 h assay). PENK concentrations are stable in plasma stored ambient to 10 days, refrigerated to at least 15 days, and frozen to at least 90 days. Results were comparable in paired SST serum and EDTA plasma. Age and sex were not associated with PENK concentrations in healthy individuals (reference interval: 36-97.5 pmol/L). Plasma PENK concentration correlated with mGFR. In a multivariate model PENK concentration, age, sex and transplant status were significant predictors of mGFR, and 49% of predicted GFR values fell within 30% of the mGFR.
Conclusions:
Both assay formats are accurate and precise for measuring clinically relevant PENK concentrations. The association of PENK concentration with mGFR is influenced by gender, age, and history of kidney transplantation. Future studies will determine if blood PENK can be used clinically to estimate GFR and/or detect AKI.
Background
Proenkephalin (PENK) has been suggested as a novel biomarker for kidney function. We investigated the diagnostic and prognostic utility of plasma PENK in comparison with neutrophil gelatinase-associated lipocalin (NGAL) and estimated glomerular filtration rates (eGFR) in septic patients.
Methods
A total of 167 septic patients were enrolled: 99 with sepsis, 37 with septic shock, and 31 with suspected sepsis. PENK and NGAL concentrations were measured and GFR was estimated by using the isotope dilution mass spectrometry traceable-Modification of Diet in Renal Disease (MDRD) Study and three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations: CKD-EPICr, CDK-EPICysC, and CKD-EPICr-CysC. The PENK, NGAL, and eGFR results were compared according to sepsis severity, presence or absence of acute kidney injury (AKI), and clinical outcomes.
Results
The PENK, NGAL, and eGFR results were significantly associated with sepsis severity and differed significantly between patients with and without AKI only in the sepsis group (all P<0.05). PENK was superior to NGAL in predicting AKI (P=0.022) and renal replacement therapy (RRT) (P=0.0085). Regardless of the variable GFR category by the different eGFR equations, PENK showed constant and significant associations with all eGFR equations. Unlike NGAL, PENK was not influenced by inflammation and predicted the 30-day mortality.
Conclusions
PENK is a highly sensitive and objective biomarker of AKI and RRT and is useful for prognosis prediction in septic patients. With its diagnostic robustness and predictive power for survival, PENK constitutes a promising biomarker in critical care settings including sepsis.
The French Intensive Care Society organized its yearly Paris International Conference in intensive care on June 18-19, 2015. The main purpose of this meeting is to gather the best experts in the field in order to provide the highest quality update on a chosen topic. In 2015, the selected theme was: "Acute Renal Failure in the ICU: from injury to recovery." The conference program covered multiple aspects of renal failure, including epidemiology, diagnosis, treatment and kidney support system, prognosis and recovery together with acute renal failure in specific settings. The present report provides a summary of every presentation including the key message and references and is structured in eight sections: (a) diagnosis and evaluation, (b) old and new diagnosis tools
Objectives:
To characterize the temporal pattern of a panel of blood and urinary biomarkers in an animal model of fecal peritonitis and recovery.
Design:
Prospective observational animal study.
Setting:
University research laboratory.
Subjects:
Male Wistar rats.
Interventions:
A fluid-resuscitated, long-term (3 d) rat model of sepsis (fecal peritonitis) and recovery was used to understand the temporal association of sepsis biomarkers in relation to systemic hemodynamics, inflammation, and renal function. At predefined time points (3, 6, 12, 24, 48, 72 hr), animals (≥ 6 per group) underwent echocardiography, blood and urine sampling, and had kidneys taken for histological analysis. Comparison was made against sham-operated controls and naïve animals.
Measurements and main results:
The systemic proinflammatory response was maximal at 6 hours, corresponding with the nadir of stroke volume. Serum creatinine peaked late (24 hr), when clinical recovery was imminent. Histological evidence of tubular injury and cell death was minimal. After a recovery period, all biomarkers returned to levels approaching those observed in sham animals. Apart from urine clusterin and interleukin-18, all other urinary biomarkers were elevated at earlier time points compared with serum creatinine. Urine neutrophil gelatinase-associated lipocalin was the most sensitive marker among those studied, rising from 3 hours. While serum creatinine fell at 12 hours, serum cystatin C increased, suggestive of decreased creatinine production.
Conclusions:
Novel information is reported on the temporal profile of a panel of renal biomarkers in sepsis in the context of systemic and renal inflammation and recovery. Insight into the pathophysiology of acute kidney injury is gleaned from the temporal change markers of renal injury (urine neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, calbindin), followed by a marker of cell cycle arrest (urine insulin-like growth factor-binding protein 7) and, finally, by functional markers of filtration (serum creatinine and cystatin C). These clinically relevant findings should have significant influence on future clinical testing.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Current reports on acute kidney injury (AKI) in the intensive care unit (ICU) show wide variation in occurrence rate and are limited by study biases such as use of incomplete AKI definition, selected cohorts, or retrospective design. Our aim was to prospectively investigate the occurrence and outcomes of AKI in ICU patients.
The Acute Kidney Injury-Epidemiologic Prospective Investigation (AKI-EPI) study was an international cross-sectional study performed in 97 centers on patients during the first week of ICU admission. We measured AKI by Kidney Disease: Improving Global Outcomes (KDIGO) criteria, and outcomes at hospital discharge.
A total of 1032 ICU patients out of 1802 [57.3 %; 95 % confidence interval (CI) 55.0-59.6] had AKI. Increasing AKI severity was associated with hospital mortality when adjusted for other variables; odds ratio of stage 1 = 1.679 (95 % CI 0.890-3.169; p = 0.109), stage 2 = 2.945 (95 % CI 1.382-6.276; p = 0.005), and stage 3 = 6.884 (95 % CI 3.876-12.228; p < 0.001). Risk-adjusted rates of AKI and mortality were similar across the world. Patients developing AKI had worse kidney function at hospital discharge with estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) in 47.7 % (95 % CI 43.6-51.7) versus 14.8 % (95 % CI 11.9-18.2) in those without AKI, p < 0.001.
This is the first multinational cross-sectional study on the epidemiology of AKI in ICU patients using the complete KDIGO criteria. We found that AKI occurred in more than half of ICU patients. Increasing AKI severity was associated with increased mortality, and AKI patients had worse renal function at the time of hospital discharge. Adjusted risks for AKI and mortality were similar across different continents and regions.
Purpose:
To assess urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein 7 ([TIMP-2]·[IGFBP7]), urinary neutrophil gelatinase-associated lipocalin (NGAL), and urinary cystatin-C as acute kidney injury predictors (AKI) exploring the association of nonrenal factors with elevated biomarker levels.
Methods:
We studied 94 patients with urine collected within 48 hours of ICU admission and no AKI at sampling. AKI was defined by the Kidney Disease: Improving Global Outcomes criteria. Predictive performance was assessed by the area under the receiver operating characteristics (ROC) curve. Associations between biomarkers and clinical factors were assessed by multivariate linear regression.
Results:
Overall, 19 patients (20%) developed AKI within 48 hours. [TIMP-2]·[IGFBP7], NGAL, or cystatin-C admission levels did not differ between patients without AKI and patients developing AKI. [TIMP-2]·[IGFBP7], NGAL, and cystatin-C were poor AKI predictors (ROC areas 0.34-0.51). Diabetes was independently associated with higher [TIMP-2]·[IGFBP7] levels (P = 0.02) but AKI was not (P = 0.24). Sepsis was independently associated with higher NGAL (P < 0.001) and cystatin-C (P = 0.003) levels.
Conclusions:
Urinary [TIMP-2]·[IGFBP7], NGAL, and cystatin-C should be used cautiously as AKI predictors in general ICU patients since urine levels of these biomarkers are affected by factors other than AKI and their performance can be poor.
Postoperative acute kidney injury (AKI) is a frequently observed complication after on-pump cardiac surgery (CS) and is associated with adverse patient outcomes. Early identification of patients at risk is essential for the prevention of AKI after CS. In this study, we analysed whether urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) combined with urine insulin-like growth factor binding protein 7 (IGFBP-7) ([TIMP-2] × [IGFBP-7]) is an adequate diagnostic test to identify early AKI after on-pump CS.
In 42 patients undergoing coronary artery bypass graft surgery, we surveyed individual risk factors for AKI and defined AKI by applying the Kidney Disease: Improving Global Outcomes (KDIGO) classification during the day of surgery and the following 2 days after surgery. Concentrations of urinary TIMP-2 multiplied by IGFBP-7 were recorded at four time points: at baseline pre-surgery, at the end of surgery, 4 hours after cardiopulmonary bypass (CPB) and at 8:00 am on the first postoperative day.
In total, 38% of the patients experienced AKI. The results showed a median baseline [TIMP-2] × [IGFBP-7] concentration of 0.3 (ng/ml)2/1,000, decreasing at the end of surgery and then increasing at the next measurement point 4 hours after CPB and further on the first postoperative day. On the first postoperative day, patients with AKI had significantly higher concentrations of [TIMP-2] × [IGFBP-7]. On the day of surgery, the concentration did not significantly differ between patients classified as KDIGO 0 or KDIGO 1 or 2. Previously published cutoff points of 0.3 and 2 were not confirmed in our study cohort.
[TIMP-2] × [IGFBP-7] concentration can be used as a diagnostic test to identify patients at increased risk of AKI after CS on the first postoperative day. At earlier time points, no significant difference in [TIMP-2] × [IGFBP-7] concentration was found between patients classified as KDIGO 0 or KDIGO 1 or 2.
Trial registration
German Clinical Trials Register (DRKS) DRKS00005457. Registered 26 November 2013.
Aims:
Acute kidney injury (AKI) occurs in up to 40% of patients undergoing cardiac surgery. Proenkephalin A 119-159 (pro-ENK) is a novel, stable surrogate biomarker for enkephalins, endogenous opioids involved in various physiological processes, including neurohormonal stress.
Material and methods:
92 patients undergoing cardiac surgery at the Veterans Affairs San Diego Healthcare System had a post-hoc analysis performed to determine the ability of pro-ENK to predict AKI as well as to compare it against other risk factors for development of AKI.
Results:
Of 92 patients, 20 patients developed AKI post-operatively. Pro-ENK levels were significantly elevated in patients who develop AKI. Log pro-ENK value pre-operatively has an odds ratio of 23.8 (p = 0.011, 95% CI = 2 - 270) in its association with AKI. Pro-ENK performs similarly to baseline creatinine in its ability to predict post-operative AKI. Importantly, pro-ENK has a strong positive correlation with creatinine (r = 0.806). Additionally, changes in pro-ENK level, from pre-operatively to 12 hours post-operatively have greatest area under curve by ROC analysis for AKI after post-operative day 1.
Conclusion:
Pro-ENK is associated with prediction of AKI in patients undergoing cardiac surgery. Pro-ENK likely has decreased clearance in the setting of AKI. However, future studies analyzing this novel biomarker should be considered to further elucidate its clinical utility and to better understand mechanisms of renal injury.
For many years, neutrophil gelatinase-associated lipocalin (NGAL) has been considered the most promising biomarker of acute kidney injury (AKI). Commercial assays and point-of-care instruments, now available in many hospitals, allow rapid NGAL measurements intended to guide the clinician in the management of patients with or at risk of AKI. However, these assays likely measure a mixture of different NGAL forms originating from different tissues. Systemic inflammation, commonly seen in critically ill patients, and several comorbidities contribute to the release of NGAL from haematopoietic and non-haematopoietic cells. The unpredictable release and complex nature of the molecule and the inability to specifically measure NGAL released by tubular cells have hampered its use a specific marker of AKI in heterogeneous critically ill populations. In this review, we describe the nature and cellular sources of NGAL, its biological role and diagnostic ability in AKI and the increasing concerns surrounding its diagnostic and clinical value. © 2014 S. Karger AG, Basel.
Neutrophil gelatinase-associated lipocalin (NGAL) may be an early marker of acute kidney injury (AKI), but elevated NGAL occurs in a wide range of systemic diseases. Because intensive care patients have high levels of comorbidity, our objective was to conduct a systematic review of the literature to evaluate the value of plasma and urinary NGAL to predict AKI in these patients. We conducted a systematic electronic literature search of MEDLINE through PubMed, EMBASE, and Cochrane Library for all English language research publications evaluating the predictive value of plasma or urinary NGAL (or both) for AKI in adult intensive care patients. Two authors independently extracted data by using a standardized extraction sheet including study characteristics, type of NGAL measurements, and type of outcome measures. The primary summary measure was area under receiver operating characteristic curve (AuROC) for NGAL to predict study outcomes. Eleven studies with a total of 2,875 (range of 20 to 632) participants were included: seven studies assessed urinary NGAL and six assessed plasma NGAL. The included studies varied in design, including observation period from NGAL sampling to AKI follow-up (range of 12 hours to 7 days), definition of baseline creatinine value, and urinary NGAL quantification method (normalizing to urinary creatinine or absolute concentration). AuROC values for the prediction of AKI ranged from 0.54 to 0.98. Five studies reported AuROC for use of renal replacement therapy ranging from 0.73 to 0.89, and four studies reported AuROC for mortality ranging from 0.58 to 0.83. There were no differences in the predictive values of urinary and plasma NGAL. The heterogeneity in study design and results made it difficult to evaluate the value of NGAL to predict AKI in intensive care patients. NGAL seems to have reasonable value in predicting use of renal replacement therapy but not mortality.
Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.
Methods: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.
Results: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P 0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.
Conclusions: Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.
Trial registration: ClinicalTrials.gov number NCT01209169.
Acute kidney injury (AKI) is associated with progression to advanced chronic kidney disease (CKD). We tested whether patients who survive AKI and are at higher risk for CKD progression can be identified during their hospital admission, thus providing opportunities to intervene. This was assessed in patients in the Department of Veterans Affairs Healthcare System hospitalized with a primary diagnosis indicating AKI (ICD9 codes 584.xx). In the exploratory phase, three multivariate prediction models for progression to stage 4 CKD were developed. In the confirmatory phase, the models were validated in 11,589 patients admitted for myocardial infarction or pneumonia during the same time frame that had RIFLE codes R, I, or F and complete data for all predictor variables. Of the 5351 patients in the AKI group, 728 entered stage 4 CKD after hospitalization. Models 1, 2, and 3 were all significant with 'c' statistics of 0.82, 0.81, and 0.77, respectively. In model validation, all three were highly significant when tested in the confirmatory patients, with moderate to large effect sizes and good predictive accuracy ('c' 0.81-0.82). Patients with AKI who required dialysis and then recovered were at especially high risk for progression to CKD. Hence, the severity of AKI is a robust predictor of progression to CKD.
To determine the reliability of creatinine as a measure of the glomerular filtration rate (GFR), we compared the simultaneous clearance of creatinine to that of three true filtration markers of graded size in 171 patients with various glomerular diseases. Using inulin (radius [rs] = 15 A) as a reference marker, we found that the fractional clearance of 99mTc-DTPA (rs = 4 A) was 1.02 +/- 0.14, while that of a 19 A rs dextran was 0.98 +/- 0.13, with neither value differing from unity. In contrast, the fractional clearance (relative to inulin) of creatinine (rs = 3 A) exceeded unity, averaging 1.64 +/- 0.05 (P less than 0.001), but could be lowered towards unity by acute blockade of tubular creatinine secretion by IV cimetidine. Cross-sectional analysis of all 171 patients revealed fractional creatinine secretion to vary inversely with GFR. This inverse relationship was confirmed also among individual patients with either deteriorating (N = 28) or remitting (N = 26) glomerular disease, who were studied longitudinally. As a result, changes in creatinine relative to inulin clearance were blunted considerably or even imperceptible. We conclude that true filtration markers with rs less than 20 A, including inulin, are unrestricted in glomerular disease, and that creatinine is hypersecreted progressively by remnant renal tubules as the disease worsens. Accordingly, attempts to use creatinine as a marker with which to evaluate or monitor glomerulopathic patients will result in gross and unpredictable overestimates of the GFR.
Background: Proenkephalin A (PENK) and its receptors are widely distributed. Enkephalins are cardiodepressive and difficult to measure directly. PENK is a stable surrogate analyte of labile enkephalins that is correlated inversely with renal function. Cardiorenal syndrome is common in acute heart failure (HF) and portends poor prognosis.
Objectives: This study assessed the prognostic value of PENK in acute HF, by identifying levels that may be useful in clinical decisions, and evaluated its utility for predicting cardiorenal syndrome.
Methods: This multicenter study measured PENK in 1,908 patients with acute HF (1,186 male; mean age 75.66 ± 11.74 years). The primary endpoint was 1-year all-cause mortality; secondary endpoints were in-hospital mortality, all-cause mortality or HF rehospitalization within 1 year, and in-hospital worsening renal function, defined as a rise in plasma creatinine ≥26.5 μmol/l or 50% higher than the admission value within 5 days of presentation.
Results: During 1-year follow-up, 518 patients died. Measures of renal function were the major determinants of PENK levels. PENK independently predicted worsening renal function (odds ratio: 1.58; 95% confidence interval [CI]: 1.24 to 2.00; p < 0.0005) with a model receiver-operating characteristic area of 0.69. PENK was associated with the degree of worsening renal function. Multivariable Cox regression models showed that PENK level was an independent predictor of 1-year mortality (p < 0.0005) and 1-year death and/or HF (hazard ratio: 1.27; 95% CI: 1.10 to 1.45; p = 0.001). PENK levels independently predicted outcomes at 3 or 6 months and were independent predictors of in-hospital mortality, predominantly down-classifying risk in survivors when added to clinical scores; levels <133.3 pmol/l and >211.3 pmol/l detected low-risk and high-risk patients, respectively.
Conclusions: PENK levels reflect cardiorenal status in acute HF and are prognostic for worsening renal function and in-hospital mortality as well as mortality during follow-up.
Background:
Proenkephalin (pro-ENK) has emerged as a novel biomarker associated with both renal function and cardiac function. However, its clinical and prognostic value have not been well evaluated in symptomatic patients with heart failure.
Methods and results:
The association between pro-ENK and markers of renal function was evaluated in 95 patients with chronic heart failure who underwent renal hemodynamic measurements including renal blood flow (RBF) and glomerular filtration rate (GFR) using(131)I-Hippuran and (125)I-Iothalamate clearances, respectively. The association between pro-ENK and clinical outcome in acute heart failure was assessed in another 1589 patients. Pro-ENK was strongly correlated with both RBF (P<0.001) and GFR (P<0.001), but not with renal tubular markers. In the acute heart failure cohort, pro-ENK was a predictor of death through 180 days, heart failure rehospitalization through 60 days, and death or cardiovascular or renal rehospitalization through day 60 in univariable analyses, but its predictive value was lost in a multivariable model, when other renal markers were entered in the model.
Conclusions:
In patients with chronic and acute heart failure, pro-ENK is strongly associated with glomerular function, but not with tubular damage. Pro-ENK provides limited prognostic information in patients with acute heart failure on top of established renal markers.
Various biomarkers of acute kidney injury (AKI) have been discovered and characterized in the recent past. These molecules can be detected in urine or blood and signify structural damage to the kidney. Clinically, they are proposed as adjunct diagnostics to serum creatinine and urinary output to improve the early detection, differential diagnosis and prognostic assessment of AKI. The most obvious requirements for a biomarker include its reflection of the underlying pathophysiology of the disease. Hence, a biomarker of AKI should derive from the injured kidney and reflect a molecular process intimately connected with tissue injury. Here, we provide an overview of the basic pathophysiology, the cellular sources and the clinical performance of the most important currently proposed biomarkers of acute kidney injury: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), interleukin 18 (IL-18), insulin-like growth factor binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinase 2 (TIMP-2), and calprotectin (S100A8/9). We also acknowledge each biomarker's advantages and disadvantages as well as important knowledge gaps and perspectives for future studies. This article is protected by copyright. All rights reserved.
High levels of proenkephalin-A (pro-ENK) have been associated with decreased eGFR in an acute setting. Here, we examined whether pro-ENK levels predict CKD and decline of renal function in a prospective cohort of 2568 participants without CKD (eGFR>60 ml/min per 1.73 m(2)) at baseline. During a mean follow-up of 16.6 years, 31.7% of participants developed CKD. Participants with baseline pro-ENK levels in the highest tertile had significantly greater yearly mean decline of eGFR (Ptrend<0.001) and rise of cystatin C (Ptrend=0.01) and creatinine (Ptrend<0.001) levels. Furthermore, compared with participants in the lowest tertile, participants in the highest tertile of baseline pro-ENK concentration had increased CKD incidence (odds ratio, 1.51; 95% confidence interval, 1.18 to 1.94) when adjusted for multiple factors. Adding pro-ENK to a model of conventional risk factors in net reclassification improvement analysis resulted in reclassification of 14.14% of participants. Genome-wide association analysis in 4150 participants of the same cohort revealed the strongest association of pro-ENK levels with rs1012178 near the PENK gene, where the minor T-allele associated with a 0.057 pmol/L higher pro-ENK level per allele (P=4.67x10(-21)). Furthermore, the T-allele associated with a 19% increased risk of CKD per allele (P=0.03) and a significant decrease in the instrumental variable estimator for eGFR (P<0.01) in a Mendelian randomization analysis. In conclusion, circulating plasma pro-ENK level predicts incident CKD and may aid in identifying subjects in need of primary preventive regimens. Additionally, the Mendelian randomization analysis suggests a causal relationship between pro-ENK level and deterioration of kidney function over time.
Heart failure (HF) patients have a poor prognosis, yet outcomes might be improved by early identification of risk. Proenkephalin (proENK) a novel biomarker, is a stable surrogate marker for endogenous enkephalins is an independent predictor of heart failure and death in patients who have suffered an acute myocardial infarction. This is the first study to evaluate the prognostic utility of this biomarker in stable ambulatory patients. We conducted a 4-year single center prospective cohort study of 200 patients who were referred for an outpatient echocardiogram. Blood samples were obtained to analyze levels of proENK at the time of the initial echocardiogram. Patients were evaluated for the combined endpoint cardiovascular related hospital admission or death. Participants with higher proENK levels were older, had higher serum createnine and lower estimated glomerular filtration rate, lower ejection fraction, and higher rates of hypertension and diabetes (p ≤ 0.009). Highest proENK tertile had a HR of 3.0 (95% CI: 1.4 - 6.7) compared with the first tertile (p < 0.007) for the primary endpoint. In conclusion, proENK demonstrated significant prognostic utility for cardiovascular related hospital admission or death.
Background: Serum creatinine concentration is widely used as an index of renal function, but this concentration is affected by factors other than glomerular filtration rate (GFR). Objective: To develop an equation to predict GFR from serum creatinine concentration and other factors. Design: Cross-sectional study of GFR, creatinine clearance, serum creatinine concentration, and demographic and clinical characteristics in patients with chronic renal disease. Patients: 1628 patients enrolled in the baseline period of the Modification of Diet in Renal Disease (MDRD) Study, of whom 1070 were randomly selected as the training sample ; the remaining 558 patients constituted the validation sample. Methods: The prediction equation was developed by stepwise regression applied to the training sample. The equation was then tested and compared with other prediction equations in the validation sample. Results: To simplify prediction of GFR, the equation included only demographic and serum variables. Independent factors associated with a lower GFR included a higher serum creatinine concentration, older age, female sex, nonblack ethnicity, higher serum urea nitrogen levels, and lower serum albumin levels (P < 0.001 for all factors). The multiple regression model explained 90.3% of the variance in the logarithm of GFR in the validation sample. Measured creatinine clearance overestimated GFR by 19%, and creatinine clearance predicted by the Cockcroft-Gault formula overestimated GFR by 16%. After adjustment for this overestimation, the percentage of variance of the logarithm of GFR predicted by measured creatinine clearance or the Cockcroft-Gault formula was 86.6% and 84.2%, respectively. Conclusion: The equation developed from the MDRD Study provided a more accurate estimate of GFR in our study group than measured creatinine clearance or other commonly used equations.
Background
Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher levels.
Background
Acute kidney injury (AKI) aggravates the prognosis of patients with sepsis. Reliable biomarkers for early detection of AKI in this setting are lacking. Enkephalins influence kidney function, and may have a role in AKI from sepsis. We utilized a novel immunoassay for plasma proenkephalin (pro-ENK), a stable surrogate marker for endogenous enkephalins, in patients hospitalized with sepsis, in order to assess its clinical utility.
Methods
In an observational retrospective study we enrolled 101 consecutive patients admitted to the emergency department (ED) with suspected sepsis. Plasma levels of pro-ENK and neutrophil gelatinase-associated lipocalin (NGAL) were evaluated at ED arrival for their association with presence and severity of AKI and 7-day mortality.
Results
pro-ENK was inversely correlated to creatinine clearance (r = −0.72) and increased with severity of AKI as determined by RIFLE (risk, injury, failure, loss of function, end-stage renal disease) stages (p
To both assess the prognostic value of proenkephalin(PENK) levels in acute myocardial infarction(AMI), using NTproBNP and GRACE score as comparators, and to identify levels that might be valuable in clinical decision making.
PENK is a stable analyte of labile enkephalins. Few biomarkers predict recurrent AMI.
We measured PENK in 1141 (820 male, mean age 66.2±SD 12.8 years) AMI patients. Endpoints were major adverse events (composite of death, MI, heart failure(HF) hospitalisation) and recurrent MI at 2 years. GRACE scoring was used for comparisons with PENK for the death and/or MI endpoint at 6 months.
During follow-up 139 patients died, with 112 HF hospitalisations and 149 recurrent AMIs. PENK levels were highest on admission and related to eGFR, LV wall motion index, gender, blood pressure and age. Multivariable Cox regression models showed PENK level was a predictor of major adverse events (hazard ratio HR 1.52(95%CI 1.19 -1.94)), death and/or AMI (HR 1.76(1.34-2.30)), death and/or HF (HR 1.67(1.24-2.25)), (p<0.001 for all) as well as recurrent AMI (HR 1.43(1.07-1.91),p<0.01). PENK levels were independent predictors of 6 month death and/or MI when compared to GRACE scores. PENK-adjusted GRACE scores reclassified patients significantly (overall category-free net reclassification improvement NRI (>0) of 21.9 (95%CI 4.5-39.4, P<0.014)). PENK levels less than 48.3pmol/L and over 91 pmol/L detected low and high-risk patients respectively.
PENK levels reflect cardio-renal status post-AMI and are prognostic for death, recurrent AMI or HF. Cut-off values define low and high risk groups, and improve risk prediction of GRACE scores.
Despite an increasing incidence of acute kidney injury in both high-income and low-income countries and growing insight into the causes and mechanisms of disease, few preventive and therapeutic options exist. Even small acute changes in kidney function can result in short-term and long-term complications, including chronic kidney disease, end-stage renal disease, and death. Presence of more than one comorbidity results in high severity of illness scores in all medical settings. Development or progression of chronic kidney disease after one or more episode of acute kidney injury could have striking socioeconomic and public health outcomes for all countries. Concerted international action encompassing many medical disciplines is needed to aid early recognition and management of acute kidney injury.
The recent evaluation of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimating the glomerular filtration rate (GFR) in multiple ethnicities has raised the question on how well this equation performs for African-American and Asian subjects. There is no doubt that serum creatinine (Scr) concentration differs between ethnicities and sexes. We show that creatinine-based equations for white populations may be inaccurate for estimating GFR in other ethnic/gender groups, especially in populations from Asia.
This study presents a mathematical analysis of the CKD-EPI-equation complemented with a literature review of median and reference values for IDMS-standardized Scr-concentrations for multiple ethnicities.
The study shows that at equal eGFR-CKD-EPI-values, the ratio of Scr between females and males equals 0.79 and between other ethnicities/sexes and white males is constant too. From this information, it is possible to calculate mean Scr-values that correspond very well with literature values directly obtained from Scr-distributions in healthy white males and females and in black males, but the discrepancy is larger for other populations.
Our results confirm the criticism that has been raised for using the CKD-EPI-equation for these ethnicities. An alternative eGFR-model is proposed based on a population-normalized Scr that needs further validation.
ACCURACYGFR estimating equations are derived from regression analysis in which the level of measured GFR is related to the serum concentration of an endogenous filtration marker and to observed clinical and demographic variables that serve as surrogates for the non-GFR determinants of the serum concentration. Age, sex, race, and body weight are surrogates for creatinine generation from muscle, which affects serum creatinine concentration independently from GFR. In principle, GFR estimating equations provide a more accurate estimate of measured GFR than the serum level of the filtration marker alone. In addition, GFR estimates are provided in the same units as measured GFR, thereby simplifying clinical decisions based on the level of kidney function. Inaccuracy of GFR estimates may be due to bias, defined as systematic deviation of estimated GFR compared with measured GFR using the reference (or “gold”) standard, or may be due to imprecision, defined as random variation (or “spread”) of estimated GFR values centered around the measured values.7Variation in creatinine assays is a major source of bias. More accurate creatinine assays, traceable to gold-standard creatinine measurements, have now replaced less accurate methods, and a creatinine standardization program has been implemented in all clinical laboratories throughout the United States.8 The effect of standardizing creatinine assays will vary among clinical laboratories, but on average will lead to lower values for serum creatinine and higher values for estimated GFR compared with measurements before standardization. The MDRD Study and CKD-EPI equations can be used with standardized creatinine.3,9 The Cockcroft-Gault equation cannot be re-expressed for standardized serum creatinine; thus, older studies that used nonstandardized creatinine assays to examine the performance of the Cockcroft-Gault equation are no longer relevant.Bias may also reflect systematic differences between development datasets and populations in which the equation will be used. These differences likely reflect differences in non-GFR determinants that are not captured by the variables used in the estimating equations. The systematic underestimation of measured GFR at higher estimated GFR by the MDRD Study equation is well known,10–12 and may reflect higher creatinine generation in healthy individuals compared with individuals with CKD in whom the MDRD Study equation was derived. This bias is reduced substantially, but not completely, by the CKD-EPI equation, which was derived from studies including people without CKD.3,13,14 In addition, the variable of black versus white or other does not capture all of the variation in creatinine generation among all racial and ethnic groups. This may be overcome in part by modifications using other race-ethnicity variables, as has been reported for use of the MDRD Study equation.15–17 A forthcoming article in AJKD introduces a modification of the CKD-EPI equation for use in Japan.18 However, even with these modifications, no equation will be free of bias in all settings and populations. Thus, knowledge of the effect of clinical conditions on non-GFR determinants of filtration markers is essential for interpretation of GFR estimates.Imprecision may reflect GFR measurement error or random variation in surrogates of non-GFR determinants. Accuracy may be improved by developing GFR estimating equations using more precise GFR measurement methods or multiple filtration markers with noncorrelated non-GFR determinants, such as cystatin C in addition to creatinine.19
Clinical assessment of kidney function is central to the practice of medicine. GFR is widely accepted as the best index of kidney function in health and disease, and accurate values are required for optimal decision making. Estimated GFR based on serum creatinine is now widely reported by clinical laboratories, and in most circumstances, estimated GFR is sufficient for clinical decision making. GFR estimates may be inaccurate in the non-steady state and in people in whom non-GFR determinants differ greatly from those in whom the estimating equation was developed. If GFR estimates are likely inaccurate or if decisions based on inaccurate estimates may have adverse consequences, a measured GFR is an important confirmatory test. Endogenous creatinine clearance is the most common method used to measure GFR in clinical practice but may be difficult to obtain or fraught with error. We review methods for GFR measurement using urinary and plasma clearance of exogenous filtration markers and focus on urinary clearance of iothalamate and plasma clearance of iohexol compared with inulin clearance. We suggest plasma clearance of nonradioactive markers be more widely implemented in clinical settings. Further research is necessary on the impact of the use of measured GFR as a confirmatory test.
Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher values.
To develop a new estimating equation for GFR: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
Cross-sectional analysis with separate pooled data sets for equation development and validation and a representative sample of the U.S. population for prevalence estimates.
Research studies and clinical populations ("studies") with measured GFR and NHANES (National Health and Nutrition Examination Survey), 1999 to 2006.
8254 participants in 10 studies (equation development data set) and 3896 participants in 16 studies (validation data set). Prevalence estimates were based on 16,032 participants in NHANES.
GFR, measured as the clearance of exogenous filtration markers (iothalamate in the development data set; iothalamate and other markers in the validation data set), and linear regression to estimate the logarithm of measured GFR from standardized creatinine levels, sex, race, and age.
In the validation data set, the CKD-EPI equation performed better than the Modification of Diet in Renal Disease Study equation, especially at higher GFR (P < 0.001 for all subsequent comparisons), with less bias (median difference between measured and estimated GFR, 2.5 vs. 5.5 mL/min per 1.73 m(2)), improved precision (interquartile range [IQR] of the differences, 16.6 vs. 18.3 mL/min per 1.73 m(2)), and greater accuracy (percentage of estimated GFR within 30% of measured GFR, 84.1% vs. 80.6%). In NHANES, the median estimated GFR was 94.5 mL/min per 1.73 m(2) (IQR, 79.7 to 108.1) vs. 85.0 (IQR, 72.9 to 98.5) mL/min per 1.73 m(2), and the prevalence of chronic kidney disease was 11.5% (95% CI, 10.6% to 12.4%) versus 13.1% (CI, 12.1% to 14.0%).
The sample contained a limited number of elderly people and racial and ethnic minorities with measured GFR.
The CKD-EPI creatinine equation is more accurate than the Modification of Diet in Renal Disease Study equation and could replace it for routine clinical use.
National Institute of Diabetes and Digestive and Kidney Diseases.
Although diagnosis and staging of acute kidney injury uses serum creatinine, acute changes in creatinine lag behind both renal injury and recovery. The risk for mortality increases when acute kidney injury accompanies sepsis; therefore, we sought to explore the limitations of serum creatinine in this setting. In mice, induction of sepsis by cecal ligation and puncture in bilaterally nephrectomized mice increased markers of nonrenal organ injury and serum TNF-alpha. Serum creatinine, however, was significantly lower in septic animals than in animals subjected to bilateral nephrectomy and sham cecal ligation and puncture. Under these conditions treatment with chloroquine decreased nonrenal organ injury markers but paradoxically increased serum creatinine. Sepsis dramatically decreased production of creatinine in nephrectomized mice, without changes in body weight, hematocrit, or extracellular fluid volume. In conclusion, sepsis reduces production of creatinine, which blunts the increase in serum creatinine after sepsis, potentially limiting the early detection of acute kidney injury. This may partially explain why small absolute increases in serum creatinine levels are associated with poor clinical outcomes. These data support the need for new biomarkers that provide better measures of renal injury, especially in patients with sepsis.
Enkephalin, a natural ligand for opiate receptors is composed of the pentapepides H-Tyr-Gly-Gly-Phe-Met-OH and H-Tyr-Gly-Gly-Phe-Leu-OH. The evidence is based on the determination of the amino acid sequence of natural enkephalin by the dansyl-Edman procedure and by mass spectrometry followed by synthesis and comparison of the natural and synthetic peptides.
Rat ventricular cardiac muscle has previously been shown to contain exceptionally high levels of preproenkephalin mRNA (ppEnk mRNA). We have recently determined that the level of ppEnk mRNA is developmentally and hormonally regulated in rat ventricular cardiac muscle tissue and in cultured myocytes (J. P. Springhorn and W. C. Claycomb. Biochem. J. 258: 73-77, 1989). We demonstrate in the current study that heart ppEnk mRNA is structurally identical at the 5' end to brain ppEnk mRNA using a ribonuclease protection assay and that heart ppEnk mRNA can be translated in vitro using a rabbit reticulocyte lysate system. In vitro synthesized preproenkephalin peptides were immunoprecipitated with a polyclonal antibody directed to the carboxy-terminal seven amino acids of preproenkephalin. We have also established by radioimmunoassay that enkephalin-containing peptides are secreted from cultured neonatal and adult rat ventricular cardiac muscle cells. This secretion is linear with respect to time and can be stimulated by phorbol 12-myristate 13-acetate (PMA) and adenosine 3',5'-cyclic monophosphate (cAMP). It was determined by column chromatography that cAMP induced neonatal rat ventricular cardiac muscle cells to secrete Met5-enkephalin-Arg6-Phe7, whereas PMA plus 3-isobutyl-1-methylxanthine induced adult rat ventricular cardiac muscle cells to secrete Met5-enkephalin. These studies establish that ventricular heart muscle ppEnk mRNA can be translated and that enkephalin peptides are secreted from ventricular cardiac muscle cells.
Administration of morphine sulfate in water-loaded rats exerts an antidiuretic effect that is dose dependent. In animals not waterloaded, the narcotic exerts a diuretic effect at a dose of 3 mg/kg sc but not at 6 and 12 mg/kg. The diuresis is characterized by an increase in urea and calcium excretion. Since, in the past, experiments dealing with the antidiuretic effect of morphine were usually carried out under hydrated conditions, the clinical significance of the effect of the narcotic on urine must be reevaluated, especially under nonwater-loading conditions.
The opiate control of vasopressin secretion in man was investigated with a long-acting analogue of met-enkephalin, DAMME (FK33-824, Sandoz). Infusion of 1 mg DAMME into water-deprived volunteers produced a diuresis which was attenuated by naloxone; there was no change in water excretion when subjects were hydrated. Plasma-immunoreactive-vasopressin failed to rise after DAMME administration, despite osmotic stimulation with hypertonic saline infusion. Opiates appear to be involved in mechanisms which suppress the osmotically mediated release of vasopressin, while opiate involvement in baroceptor-mediated release may be quite different.
Studies were performed to define the responses of plasma met-enkephalin to various endocrine and pathological stimuli and to determine the relationship between plasma β-endorphin and met-enkephalin. During insulin-induced hypoglycaemia ACTH, β-LPH and β-endorphin immunoreactivity rose in parallel, but plasma met-enkephalin did not change significantly. Sephadex G75 chromatography of samples taken at the time of the peak response (45 min) confirmed the rise in both β-LPH and β-endorphin. During administration of dexamethasone, 0·5mg 6 hourly for 48 h, plasma cortisol and ACTH became undetectable at 24 h, and β-LPH and β-endorphin fell significantly by 24 h and were undetectable by 48 h; plasma met-enkephalin, however, showed no significant change. Nine adrenalectomized patients with Cushing's disease and four patients with Addison's disease had elevated plasma ACTH, β-LPH and β-endorphin but normal plasma met-enkephalin levels. Each of ten patients with renal failure had markedly elevated plasma met-enkephalin immunoreactivity which co-eluted with synthetic met-enkephalin on BioGel P4 chromatography. Trypsin and carboxypeptidase-B digestion of the P4 chromatography fractions generated met-enkephalin immunoreactivity in earlier fractions, indicating the presence of a potential high molecular weight met-enkephalin precursor.
The results imply that different control mechanisms govern β-endorphin and met-enkephalin plasma levels and that the adrenal is not the only source of plasma met-enkephalin. The elevated levels of met-enkephalin in renal failure may be due to impaired clearance of met-enkephalin or of its precursor or to increased met-enkephalin production.
In studies on the progression of chronic renal failure the measurement of GFR must be very reliable. Sequential determination of GFR using the renal clearances of exogenous tracers such as inulin or iothalamate is the most accepted method. However, because of inaccuracies in urine collection, intratest variation, and thus intertest variation, of these clearances is considerable. This has a negative impact on the precision of long-term slope estimations. A previously described method of GFR determination on the basis of simultaneous infusion of 131I-hippuran and 125I-iothalamate corrects for inaccurate urine collection. To study whether this correction method improves the precision of the GFR slope measurement, this study analyzed longitudinal GFR data obtained in 71 patients with renal disease during a follow-up of 84 to 180 wk (477 renal function studies). All GFR were calculated by using both the standard renal clearance method and the correction method. The intratest and intertest coefficient of variation was significantly smaller for the correction method compared with the standard method (1.93 +/- 0.20 versus 8.48 +/- 1.66% P < 0.0005; and 2.88 +/- 0.32 versus 5.12 +/- 0.66%, P < 0.005, respectively). As a result, the precision of the GFR slope estimation was significantly better with the correction method compared with the standard method (error of the slope, 1.63 +/- 1.09 versus 2.35 +/- 2.36 mL/min per yr, P < 0.01). This improvement in precision of the slope by using the correction method reduces the necessary sample size needed to detect a GFR slope difference between interventions to about 30% of that needed when using the standard method. It is concluded that the precision of GFR measurements is improved by using correction for inaccurate urine collection with concomitant 131I-hippuran clearance.
1. Over the past 50 years considerable evidence has been reported suggesting that endogenous opioids participate in the control of renal function.
2. Exogenous administration of opioids produces profound changes in the renal excretion of water and sodium.
3. Opioids produce changes in urine output and urine sodium excretion by multiple integrated neural and hormonal mechanisms within the periphery, central nervous system and kidneys.
4. Although opioid antagonist administration does not consistently reveal an action of endogenous opioid systems on renal function, this may result from the quiescent nature of the endogenous opioid system under basal conditions.
5. Manipulations that activate endogenous opioid systems have begun to reveal important, previously unrecognized mechanisms that control kidney function and can enhance renal tubular sodium reabsorption in normal and potentially pathological states.
Studies were performed in conscious Sprague-Dawley rats to characterize the changes in renal excretory function produced by activation of delta opioid systems. The intravenous infusion of 50 microgram/kg/min, BW373U86 (BW), a nonpeptide delta opioid receptor agonist, produced a significant increase in urine flow rate and urinary sodium excretion. The infusion of BW at a dose of 30 microgram/kg/min produced diuresis without affecting urinary sodium excretion. In contrast, BW did not alter either renal excretory parameter at a dose of 10 microgram/kg/min. The renal responses produced by BW occurred without changes in heart rate or mean arterial blood pressure. The diuretic and natriuretic responses produced by the i.v. infusion of BW (50 microgram/kg/min) were prevented by pretreatment of animals with the selective delta opioid receptor antagonist, naltrindole (1 mg/kg, i.v.). When administered alone, naltrindole (1 mg/kg, i.v.) failed to change any systemic cardiovascular or renal excretory parameter. In other groups of animals, the peripheral administration of the delta opioid receptor agonist, SNC80, also evoked a profound diuretic and natriuretic response (naltrindole sensitive) similar to that produced by BW. In contrast to these findings, the diuretic and natriuretic response produced by BW infusion (30 or 50 microgram/kg/min, i.v.) was abolished in rats having undergone chronic bilateral renal denervation. Together, these results demonstrate that the peripheral administration of BW373U86 or SNC80 produce marked diuretic and natriuretic responses in conscious Sprague-Dawley rats via a delta opioid receptor pathway and that intact renal nerves are required for mediating these responses. Although endogenous delta opioid systems do not appear to exert a tonic influence under basal conditions, these findings suggest that delta opioid pathways may evoke significant changes in renal excretory function under conditions in which these systems are activated.
Serum creatinine concentration is widely used as an index of renal function, but this concentration is affected by factors other than glomerular filtration rate (GFR).
To develop an equation to predict GFR from serum creatinine concentration and other factors.
Cross-sectional study of GFR, creatinine clearance, serum creatinine concentration, and demographic and clinical characteristics in patients with chronic renal disease.
1628 patients enrolled in the baseline period of the Modification of Diet in Renal Disease (MDRD) Study, of whom 1070 were randomly selected as the training sample; the remaining 558 patients constituted the validation sample.
The prediction equation was developed by stepwise regression applied to the training sample. The equation was then tested and compared with other prediction equations in the validation sample.
To simplify prediction of GFR, the equation included only demographic and serum variables. Independent factors associated with a lower GFR included a higher serum creatinine concentration, older age, female sex, nonblack ethnicity, higher serum urea nitrogen levels, and lower serum albumin levels (P < 0.001 for all factors). The multiple regression model explained 90.3% of the variance in the logarithm of GFR in the validation sample. Measured creatinine clearance overestimated GFR by 19%, and creatinine clearance predicted by the Cockcroft-Gault formula overestimated GFR by 16%. After adjustment for this overestimation, the percentage of variance of the logarithm of GFR predicted by measured creatinine clearance or the Cockcroft-Gault formula was 86.6% and 84.2%, respectively.
The equation developed from the MDRD Study provided a more accurate estimate of GFR in our study group than measured creatinine clearance or other commonly used equations.
In human subjects, the assessment of renal function and of its changes by interventions is limited to the measurement of glomerular filtration rate (GFR), renal blood flow and the estimation of proteinuria. In humans, GFR can be determined exactly by measuring the clearance of an ideal filtration marker, such as inulin. The classic method of measuring inulin clearance in humans includes constant intravenous infusion of the compound and timed collections of urine. In order to avoid the need for timed urine collections, a number of alternative procedures have been devised. All these methods only use determinations of inulin in plasma or serum. From these, the total body inulin clearance is obtained using pharmacokinetic calculations. In order to measure total body clearance, usually called plasma clearance, inulin is either given as a constant intravenous infusion or as a bolus infusion. Both procedures overestimate GFR because of incomplete distribution of inulin during the study periods. The error may be minimized by using model-independent pharmacokinetic calculations. Unlike inulin, creatinine is not a perfect filtration marker. This is because the substance is not only eliminated by glomerular filtration but also by tubular secretion. The extent of tubular creatinine secretion is not constant in various individuals. Serum creatinine concentration is a commonly used measure of renal function in clinical practice. This parameter is determined both by the renal elimination and by the production of the compound. Differences in creatinine production among subjects and over time in a single individual may occur because of changes in muscle mass. Radioisotopic filtration markers can easily and accurately be measured in plasma and serum. Using this method, the plasma concentration-time curve of these compounds can easily be studied after intravenous bolus injection. From the plasma concentration-time curves obtained, the total body clearance (plasma clearance) of the substances can be calculated using pharmacokinetic models. Most frequently, 125l-iothalamate, 99mTc-diethylenethiaminepenta-acetic acid and 51Cr-ethylenediaminetetra-acetic acid are used for the estimation of GFR in humans. The total body clearance of all these filtration markers overestimates GFR. The error induced by this phenomenon is particularly relevant at low levels of GFR. In recent years, iohexol has been used as a filtration marker. The substance can be measured in plasma, serum and urine using high-performance liquid chromatography. So far, good agreement has been shown for GFR determined by the classic inulin clearance and by the iohexol plasma clearance. Screening for proteinuria is commonly performed using reagent test strips. Quantitative measurements of marker proteins can be used to estimate the extent and the site of damage in the nephron. These measurements may be used to estimate the progression of renal disease and the response to therapeutic interventions. Of particular interest is the degree of albuminuria which indicates nephropathy in diabetic patients and end-organ damage in patients with hypertension.
Polypeptides in human cerebrospinal fluid (CSF), isolated by phase separation in chloroform-methanol-water and reversed-phase HPLC, were characterised by sequence analysis and mass spectrometry. This identified the presence of peptide fragments of testican, neuroendocrine specific protein VGF, neuroendocrine protein 7B2, chromogranin B/secretogranin I, chromogranin A, osteopontin, IGF-II E-peptide and proenkephalin. The majority of these fragments were generated by proteolysis at dibasic sites, suggesting that they are derived by activities related to prohormone convertase(s). Several of the fragments have previously not been detected, and their functions in CSF or elsewhere are unknown. A characteristic feature of all these fragments is a very high content of acidic residues, in particular glutamic acid. In addition to the fragments of neuroendocrine proteins, endothelin-binding receptor-like protein 2, ribonuclease 1, IGF-binding protein 6, albumin, alpha1-acid glycoprotein 1, prostaglandin-H2 D-isomerase, apolipoprotein A1, transthyretin, beta2-microglobulin, ubiquitin, fibrinopeptide A, and C4A anaphylatoxin were found.
Opiates have been used for thousands of years in the form of opium for relief of pain or fever and to induce sleep. However, it was only in the 1970s that the endogenous ligands for the opiate receptors were identified and termed opioid peptides. Opioid peptides activate G protein-coupled receptors in the central and autonomic nervous system, with marked effects on the regulation of pain perception, body temperature, respiration, heart rate and blood pressure. Cardiovascular regulatory effects of endogenous opioids were initially considered to originate from neural centres in the central nervous system, facilitating a regulatory role in neuro-transmission, as demonstrated by the presynaptic co-release from sympathetic neurones of norepinephrine with enkephalin or acetylcholine with enkephalin. However, opioid peptides of myocardial origin have also recently been shown to play a key role in local regulation of the heart. This brief review highlights the key features of the enkephalin opioids in the heart and the current understanding of their role in development, ageing, cardioprotection, hypertension, hypertrophy, and heart failure.
In this report, we describe a newly developed sandwich immunoassay using antibodies against the proenkephalin A 119-159 peptide (PENK A 119-159). PENK A 119-159 immunoreactivity was detectable in the circulation of human blood donors and in cerebrospinal fluid (CSF) of patients without a neurologic disorder. The concentration was about 100 times higher in CSF than in serum. Analytical reversed phase HPLC revealed that PENK A 119-159 is the main immunoreactivity in human circulation and CSF. Moreover, PENK A 119-159 is stable in vitro for at least 48 h at room temperature as compared to the low stability of the peptides methionine- and leucine-enkephalin. This suggests the use of PENK A 119-159 measurement as surrogate molecule for the release of the mature peptides derived from proenkephalin A.
Enkephalins are opioid peptides that are found at high levels in the brain and endocrine tissues. Studies have shown that enkephalins play an important role in behavior, pain, cardiac function, cellular growth, immunity, and ischemic tolerance. Our global hypothesis is that enkephalins are released from non-neuronal tissues in response to brief ischemia or exercise, and that this release contributes to cardioprotection. To identify tissues that could serve as potential sources of enkephalins, we used real-time PCR, Western blot analysis, ELISA, immunofluorescence microscopy, and ex vivo models of enkephalin release. We found widespread expression of preproenkephalin (pPENK) mRNA and production of the enkephalin precursor protein proenkephalin (PENK) in rat and mouse tissues, as well as in tissues and cells from humans and pigs. Immunofluorescence microscopy with anti-enkephalin antisera demonstrated immunoreactivity in rat tissues, including heart and skeletal muscle myocytes, intestinal and kidney epithelium, and intestinal smooth muscle cells. Finally, isolated tissue studies showed that heart, skeletal muscle, and intestine released enkephalins ex vivo. Together our studies indicate that multiple non-neuronal tissues produce PENK and release enkephalins. These data support the hypothesis that non-neuronal tissues could play a role in both local and systemic enkephalin-mediated effects.
Serum cystatin C increasingly is used as a marker of glomerular filtration rate and cardiovascular risk. However, information for serum cystatin C levels in the general population, specifically across a wide age range and different ethnicities, is lacking.
To determine nationally representative serum cystatin C levels, estimate the prevalence of increased cystatin C levels in the general population, and identify factors associated with increased cystatin C levels.
Cross-sectional survey.
A nationally representative subsample of 7,596 participants aged 12 years or older in the Third National Health and Nutrition Examination Survey conducted in 1988-1994.
Age, sex, race/ethnicity, risk factors for chronic kidney disease.
Continuous serum cystatin C levels and serum cystatin C level greater than 1.12 mg/L.
Cystatin C was measured in 2006 from stored sera by using an automated particle-enhanced nephelometric assay.
Overall median serum cystatin C level was 0.85 mg/L. Median cystatin C levels increased steeply with age and were greater in males and non-Hispanic white persons, even in a healthy subgroup of 20- to 39-year-olds. Prevalences of increased serum cystatin C levels (>1.12 mg/L) were 1%, 41%, and greater than 50% in all persons aged younger than 20 years, 60 years or older, and 80 years or older. In persons aged 60 years and older, older age, non-Hispanic white ethnicity, hypertension, current smoking, lower levels of education and high-density lipoprotein cholesterol, and increased body mass index, C-reactive protein, and triglyceride values were associated significantly with increased serum cystatin C levels.
No measured glomerular filtration rate, single measurement of cystatin C, cross-sectional study design.
Serum cystatin C level is related to sex and ethnicity, even in young healthy individuals. The prevalence of increased cystatin C levels increases dramatically with age, reaching greater than 50% after the age of 80 years in both sexes and all ethnic groups.
- R Bellomo
- C Ronco
- R L Mehta
- P Asfar
- J Boisrame-Helms
- M Darmon
Bellomo R, Ronco C, Mehta RL, Asfar P, Boisrame-Helms
J, Darmon M, et al. Acute kidney injury in the ICU:
from injury to recovery: reports from the 5th Paris
International Conference. Ann Intensive Care 2017;71:
49.
IGFBP-7/TIMP-2 and pro-enkephalin levels in acute kidney injury: results from the FROG ICU study in AKI & CRRT
- M Legrand
Legrand M. IGFBP-7/TIMP-2 and pro-enkephalin levels in
acute kidney injury: results from the FROG ICU study in
AKI & CRRT 2017. San Diego (CA); 2017.
Plasma proenkephalin to monitor kidney function in critically ill sepsis patients [abstract] in AKI & CRRT 2017
- G Leijte
Leijte G. Plasma proenkephalin to monitor kidney
function in critically ill sepsis patients [abstract] in AKI &
CRRT 2017. San Diego (CA); 2017.
Clinical correlates and prognostic value of proenkephalin in acute and chronic heart failure
- Y Matsue
- J M Ter Maaten
- J Struck
- M Metra
- O' Connor
- C M Ponikowski
Matsue Y, Ter Maaten JM, Struck J, Metra M, O'Connor
CM, Ponikowski P, et al. Clinical correlates and prognostic
value of proenkephalin in acute and chronic heart
failure. J Card Fail 2017;233:231-9.
Plasma penkid to monitor kidney function following cardiac surgery
- E Peters
Peters E. Plasma penkid to monitor kidney function
following cardiac surgery [abstract] in AKI & CRRT 2017.
San Diego (CA); 2017.