Article

Proenkephalin (PENK) as a Novel Biomarker for Kidney Function

November 2017
The Journal of Applied Laboratory Medicine 2(3):400-412

DOI:10.1373/jalm.2017.023598

Authors:

Joachim Struck

Alan Wu

UCSF

Alexander Zarbock

University of Münster

Show all 13 authorsHide

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.

Proenkephalin-A secreted by renal proximal tubules functions as a brake in kidney regeneration

Article

Full-text available

Nov 2023

Organ regeneration necessitates precise coordination of accelerators and brakes to restore organ function. However, the mechanisms underlying this intricate molecular crosstalk remain elusive. In this study, the level of proenkephalin-A (PENK-A), expressed by renal proximal tubular epithelial cells, decreases significantly with the loss of renal proximal tubules and increased at the termination phase of zebrafish kidney regeneration. Notably, this change contrasts with the role of hydrogen peroxide (H2O2), which acts as an accelerator in kidney regeneration. Through experiments with penka mutants and pharmaceutical treatments, we demonstrate that PENK-A inhibits H2O2 production in a dose-dependent manner, suggesting its involvement in regulating the rate and termination of regeneration. Furthermore, H2O2 influences the expression of tcf21, a vital factor in the formation of renal progenitor cell aggregates, by remodeling H3K4me3 in renal cells. Overall, our findings highlight the regulatory role of PENK-A as a brake in kidney regeneration.

Plasma Pro-Enkephalin A and Incident Cognitive Impairment: The Reasons for Geographic and Racial Differences in Stroke Cohort

Article

Full-text available

Jun 2023

Background Cardiovascular disease is a risk factor for cognitive impairment. Evidence links both lower and higher concentration of the circulating opioid pro‐enkephalin A (PENK‐A) with stroke risk. We studied the association of plasma PENK‐A with incident cognitive impairment. Methods and Results REGARDS (Reasons for Geographic and Racial Differences in Stroke) is a prospective cohort study of 30 239 adults enrolled from 2003 to 2007. Baseline PENK‐A was measured in a nested case–control study of 462 participants who developed cognitive impairment over 4.7 years, and 556 controls. Logistic regression and spline plots adjusted for confounders estimated odds ratios (ORs) of cognitive impairment by baseline PENK‐A. Interaction terms tested for differences in associations by age, sex, and race. Baseline PENK‐A was comparable between cases and controls. There were significant differences in the association of PENK‐A with cognitive impairment by sex and age (adjusted P =0.003 and 0.06, respectively). In women but not men, spline plots showed that higher and lower PENK‐A were associated with decreased odds of cognitive impairment (ORs for 10th and 90th percentiles versus median, 0.65 [95% CI, 0.43–0.96] and 0.64 [95% CI, 0.41–0.99]), with no difference by age. In men ≥65 years of age but not younger men, higher PENK‐A was associated with decreased odds for cognitive impairment (OR for fourth versus first quartile 0.47 [95% CI, 0.22–0.99]); this pattern was not confirmed with spline plotting. Conclusions High and low levels of circulating opioid PENK‐A were associated with decreased odds of future cognitive impairment in specific subgroups. Additional research is warranted to understand the biology underlying this association and the observed differences by sex.

Localization and characterization of Proenkephalin-A as a potential biomarker for kidney disease in murine and human kidneys

Article

Nov 2022

Introduction Exact measurement of renal function is essential for the treatment of patients. Elevated serum-creatinine levels, while established are influenced by other parameters and show a significant time-lag. This drives the search for novel biomarkers of renal function and injury. Beside Lipocalin-2 and kidney-injury-molecule-1(KIM-1), the endogenous opioid precursor proenkephalin-A(Penk) has recently emerged as a promising marker for renal function. But the cellular origin and regulation of Penk outside the brain has not yet been investigated in depth. Materials and Methods This study characterizes the cellular origin of Penk expression with high resolution in-situ hybridization in two models of renal fibrosis in mice and human tissue. Results Interstitial cells are the main expression site for renal Penk. This classifies Penk as biomarker for interstitial damage as opposed to tubular damage markers like Lipocalin-2 and KIM-1. Furthermore, our data indicate that renal Penk expression is not regulated by classical profibrotic pathways. Discussion This study characterizes changing Penk expression in the kidneys. The similarity of Penk expression across species gives rise to further investigations into the function of Penk in healthy and injured kidneys. Conclusion Penk is a promising biomarker for interstitial renal damage that warrants further studies to utilize its predictive potential.

Proenkephalin and the risk of new‐onset heart failure: data from prevention of renal and vascular end‐stage disease

Article

Full-text available

Oct 2021
CLIN CARDIOL

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.

Clinical performance of proenkephalin A 119-159 for the early diagnosis of acute kidney injury in patients with sepsis or septic shock

Preprint

Full-text available

Oct 2024

Background: Sepsis-associated acute kidney injury (AKI) is a severe condition associated with unfavorable outcomes in critically ill patients, not least because of its delayed diagnosis and management due to limitations in the current standard of care. We aimed to evaluate the performance of sphingotest penKid for the early diagnosis of AKI in patients with sepsis or septic shock. Methods: Plasma Proenkephalin A 119-159 (penKid) was measured in 120 healthy subjects and 529 critically ill sepsis patients. Subgroup analyses were performed for patients with and without a history of heart failure or hypertension. The clinical performance for the diagnosis of AKI within 48 hours (AKI48h) was calculated using the upper limit of the penKid reference range. To improve clinical decision-making, interpretation bands and likelihood ratios for optimized rule-in and rule-out performance were established. Results: Of the 529 patients with sepsis or septic shock, 328 were male (62%), and the median age was 66 (interquartile range 56-75) years. Two hundred thirty-four (44%) patients were diagnosed with AKI48h, and those patients presented increased penKid levels on intensive care unit admission compared with patients without AKI48h, with an area under the curve of 0.87 (95% confidence interval [CI] 0.84-0.90, p<0.0001). A penKid cut-off of 89 pmol/L, corresponding to the 97.5th percentile in the healthy reference population, resulted in 72% sensitivity (95% CI 66-77%), 83% specificity (95% CI 78-87%), 77% positive predictive value (95% CI 71-82%), 79% negative predictive value (95% CI 74-83%), a positive likelihood ratio of 4.2, and a negative likelihood ratio of 0.34 to diagnose AKI48h. An improved performance was obtained when patients with a history of chronic heart failure and/or hypertension were excluded. PenKid cutoff values of 54 pmol/L (>92% sensitivity) and 105 pmol/L (>92% specificity) were derived to establish actionable interpretation bands for diagnostic rule-in and rule-out. Conclusions: The sphingotest penKid assay can facilitate an early diagnosis of AKI up to 48 hours before the KDIGO criteria are met. Based on the present results, the assay was registered as an aid in the early diagnosis of AKI in patients with sepsis or septic shock.

Advances in laboratory detection of acute kidney injury

Article

Full-text available

Jun 2022

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 as a new biomarker for pediatric acute kidney injury - Reference values and performance in children under one year of age

Article

Full-text available

Jun 2020
CLIN CHEM LAB MED

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.

Novel biomarkers for predicting successful liberation of renal replacement therapy for acute kidney injury: a systematic review

Article

Full-text available

May 2025

Proenkephalin A 119-159 in Kidney Transplantation: A Novel Biomarker for Superior Tracking of Graft Function Trajectories

Article

Full-text available

May 2025
TRANSPL INT

Accurate assessment of graft function trajectories after kidney transplantation is essential for optimizing patient management. Slow graft function (SGF) and delayed graft function (DGF) are associated with impaired recovery, yet current diagnostic tools lack granularity for timely risk stratification. Proenkephalin A 119-159 (penKid) may improve graft function assessment, enhancing risk stratification for SGF, DGF, and associated outcomes. This prospective study evaluated 159 kidney transplant recipients at Heidelberg University Hospital to compare plasma penKid levels with current risk-indicators for poor (functional) graft trajectories. Validation was conducted using an independent transplant cohort from Sydney. Clinical relevance of biomarker-indicated changes in graft function was assessed using multivariable regression models and AUROC analyses. From day one post-transplant, penKid outperformed serum creatinine (SCr) in identifying functional trajectories associated with DGF (AUROC penKid: 0.87 vs. SCr: 0.56) and differentiated SGF from DGF (AUROC penKid: 0.79 vs. SCr: 0.33) up to eight days earlier. PenKid further demonstrated superior granularity in assessing DGF severity and 30-day outcomes. After adjustment for common risk factors, penKid remained the strongest risk stratifier for all tested outcomes. PenKid is a superior biomarker for earlier assessment of graft function trajectories, offering potential to enhance personalized care and clinical trial designs in kidney transplantation.

Biomarkers as Beacons: Illuminating Sepsis-Associated Hepato-Renal Injury

Article

Full-text available

May 2025
INT J MOL SCI

Sepsis, defined as a dysregulated host response to infection, is one of the leading causes of mortality worldwide. It unleashes in the organism a cascade of molecules, cytokines, and proteins which leads to an inflammatory storm. If this response to infection is uncontrolled, any organ is susceptible to damage. Acute kidney injury (AKI) is one of the most frequent organ dysfunctions in septic patients, and while it can be reversible, its presence leads to a higher burden of morbidity and mortality. While serum creatinine is essential in evaluating kidney function, the pathophysiology of AKI is not completely elucidated, and a plethora of novel biomarkers have been studied in the hope of an early diagnosis and fast treatment. While the liver is not as affected by sepsis, it plays an important role as a guardian by providing acute-phase proteins, activating neutrophils, and controlling iron balance. Acute liver failure (ALF) could impair the organism’s capacity to contain and eliminate pathogens. Some molecules have been associated with either AKI or ALF, although biomarkers specific for organ dysfunction are difficult to validate. The aim of this review is to understand the role of several molecules in the pathophysiology of sepsis and their clinical ability for diagnosing or predicting sepsis-induced hepato-renal dysfunction.

Renal tubular epithelial cells as an easily accessible biomarker for diagnosing AKI post cardiac surgery

Article

May 2025
INTENS CARE MED

Acute kidney injury (AKI) is a common clinical complication of cardiac surgeries. Although urinary particle analysis is useful for differentiating AKI, its value in AKI diagnosis has not yet been well described. We sought to determine the contribution of urinary particle analysis to the diagnosis of AKI. Two-hundred and thirty-nine adult patients were prospectively included after cardiac surgery. The diagnostic performance of urinary particle analysis at different time points after intensive care unit (ICU) admission was evaluated. AKI was diagnosed and classified according to the KDIGO definitions. Urinary particles, including renal tubular epithelial cells (RTEC) and non-hyaline casts, Nephrocheck®, urinary alpha-1-microglobulin and urinary γ-glutamyltransferase (GGT) levels were measured at 4, 12 and 24 h after ICU admission and evaluated against different endpoints. Of the 239 patients included, 39 (16.3%) had AKI stage 1, 121 (50.6%) had stage 2, and 15 (6.3%) stage 3. In the early postoperative period, urinary alpha-1-microglobulin and Nephrocheck® were good predictors of AKI stage ≥ 1 within 48 h after ICU admission (primary endpoint) and AKI stage ≥ 2 (1st secondary endpoint), respectively. Furthermore, at 12 h and 24 h after ICU admission, RTEC had the highest predictive value for AKI up to 48 h after ICU admission based on serum creatinine alone and for all AKI criteria up to 7 days after ICU admission. Correction of the obtained counts for the hydration status did not improve the obtained results. Urinary particle analysis with RTEC is useful for the early diagnosis of AKI following cardiac surgery, especially at 12 h and 24 h after ICU admission.

Renal tubular epithelial cells as an easily accessible biomarker for diagnosing AKI post cardiac surgery

Preprint

Full-text available

Jan 2025

Purpose Acute kidney injury (AKI) is a common clinical complication of cardiac surgeries. Although urinary particle analysis is useful for differentiating AKI, its value in AKI diagnosis has not yet been well described. We sought to determine the contribution of urinary particle analysis to the diagnosis of AKI. Methods Two-hundred and thirty-nine adult patients were prospectively included after cardiac surgery. The diagnostic performance of urinary particle analysis at different time points after intensive care unit (ICU) admission was evaluated. AKI was diagnosed and classified according to the KDIGO definitions. Urinary particles, including renal tubular epithelial cells (RTEC) and non-hyaline casts, Nephrocheck®, urinary alpha-1-microglobulin and urinary γ-glutamyltransferase (GGT) levels were measured at 4, 12 and 24h after ICU admission and evaluated against different endpoints. Results Of the 239 patients included, 41 (17.1%) had AKI stage 1, 118 (49.2%) had stage 2, and 16 (6.7%) stage 3. In the early postoperative period, urinary alpha-1-microglobulin and Nephrocheck® were good predictors of AKI stage ≥1 within 48h after ICU admission (primary endpoint) and AKI stage ≥2 (1 st secondary endpoint), respectively. Furthermore, at 12h and 24h after ICU admission, RTEC had the highest predictive value for AKI up to 48h after ICU admission based on serum creatinine alone and for all AKI criteria up to 7d after ICU admission. Correction of the obtained counts for the hydration status did not improve the obtained results. Conclusion Urinary particle analysis with RTEC is useful for the early diagnosis of AKI following cardiac surgery, especially at 12h and 24h after ICU admission.

Advances in the diagnosis of early biomarkers for acute kidney injury: a literature review

Article

Full-text available

Mar 2025
BMC Nephrol

Acute kidney injury (AKI) is a critical condition with diverse manifestations and variable outcomes. Its diagnosis traditionally relies on delayed indicators such as serum creatinine and urine output, making early detection challenging. Early identification is essential to improving patient outcomes, driving the need for novel biomarkers. Recent advancements have identified promising biomarkers across various biological processes. Tubular injury markers, including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), and liver-type fatty acid-binding protein (L-FABP), offer insights into early tubular damage. Inflammatory and repair-associated biomarkers, such as interleukin-18 (IL-18), monocyte chemotactic protein-1 (MCP-1), osteopontin (OPN), and C-C motif chemokine ligand 14 (CCL14), reflect ongoing injury and recovery processes. Additionally, stress and repair markers like tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP-7), alongside filtration markers such as cystatin C (CysC) and proenkephalin (PenKid®) e.tal, further enhance diagnostic precision. Oxidative stress-related markers, including Superoxide Dismutase 1 (SOD1), also contribute valuable information. Emerging candidates, such as microRNAs, soluble urokinase plasminogen activator receptor (SuPAR), and chitinase-3-like protein 1 (CHI3L1), hold substantial promise for AKI detection and prognosis. This review summarizes the progress in AKI biomarker research, highlighting their clinical utility and exploring their potential to refine early diagnosis and management strategies. These findings offer a new perspective for integrating novel biomarkers into routine clinical practice, ultimately improving AKI care.

Can Novel Biomarkers Effectively Predict Acute Kidney Injury in Liver or Kidney Transplant Recipients?

Article

Full-text available

Nov 2024
INT J MOL SCI

Acute kidney injury (AKI) constitutes a common complication associated with liver or kidney transplantation, which may significantly impact the graft condition and perioperative mortality. Current AKI diagnostic criteria based on serum creatinine (sCr) and urine output alterations are widely utilized in routine clinical practice. However, the diagnostic value of sCr may be limited by various confounding factors, including age, sex, reduced or increased muscle mass, and pre-existing chronic kidney disease (CKD). Furthermore, sCr is rather a late indicator of AKI, as its concentration tends to increase only when the severity of the injury is enough to decrease the estimated glomerular filtration rate (eGFR). Recent expertise highlights the need for novel biomarkers in post-transplantation AKI diagnosis, prediction of event-associated mortality, or evaluation of indications for renal replacement treatment (RRT). Over the last decade, the diagnostic performance of various AKI biomarkers has been assessed, among which some showed the potential to outperform sCr in AKI diagnosis. Identifying susceptible individuals, early diagnosis, and prompt intervention are crucial for successful transplantation, undisturbed graft function in long-term follow-up, and decreased mortality. However, the research on AKI biomarkers in transplantation still needs to be explored. The field lacks consistent results, rigorous study designs, and external validation. Considering the rapidly growing prevalence of CKD and cirrhosis that are associated with the transplantation at their end-stage, as well as the existing knowledge gap, the aim of this article was to provide the most up-to-date review of the studies on novel biomarkers in the diagnosis of post-transplantation AKI.

Proenkephalin A 119-159 (penKid) and mortality in stable patients at high cardiovascular risk

Article

Full-text available

Sep 2024

Background Proenkephalin A 119–159 (penKid) is a novel blood biomarker for real-time assessment of kidney function and was found to be independently associated with worsening kidney function and mortality. A novel penKid-based estimated GFR-equation (eGFRPENK-Crea), outperforms current creatinine-based eGFR equations in predicting iohexol or iothalamate plasma clearance based measured GFR (mGFR). In this study, we aimed to evaluate the predictive value of penKid and eGFRPENK-Crea for all-cause mortality in stable patients at high cardiovascular risk. Methods Circulating penKid levels were assessed in 615 stable patients hospitalized at the Department of Cardiology at University Hospital Aachen, Germany. The endpoint was all-cause mortality; follow up was 3 years. Results PenKid levels were higher in 46 non-survivors (58.8 [IQR 47.5–85.0] pmol/L) compared to 569 survivors (43.8 [IQR 34.0–58.0] pmol/L; P < 0.0001). Univariable cox regression analyses found penKid and eGFRPENK-Crea to be associated with all-cause mortality (C index: 0.703, χ2: 33.27, P < 0.00001; C index: 0.716, χ2: 36.51, P < 0.00001). This association remained significant after adjustment for significant baseline parameters including age, smoking, chronic heart failure, use of diuretics, leucocytes, body mass index, sex and creatinine (C index: 0.799, χ2: 72.06, P < 0.00001). Importantly, penKid provided significant added value on top of eGFRCKD-EPI 2021 (eGFRCKD-EPI 2021: C index: 0.716, χ2: 34.21; eGFRCKD-EPI 2021 + penKid: C index: 0.727, χ2: 40.02; Delta Chi2: 5.81; all P < 0.00001) for all-cause mortality prediction in our cohort. Conclusions PenKid levels and eGFRPENK-Crea is associated with all-cause mortality within a three-year follow-up period and the addition of penKid on top of eGFRCKD-EPI 2021 provided significant added value in mortality prediction.

Proenkephalin Improves Cardio-Renal Risk Prediction in Acute Coronary Syndromes: The KID-ACS Score

Article

Aug 2024
EUR HEART J

Background and Aims Circulating proenkephalin (PENK) is a stable endogenous polypeptide with fast response to glomerular dysfunction and tubular damage. This study examined the predictive value of PENK for renal outcomes and mortality in patients with acute coronary syndromes (ACS). Methods Proenkephalin was measured in plasma in a prospective multicentre ACS cohort from Switzerland (n=4787) and in validation cohorts from the UK (n=1141), Czechia (n=927), and Germany (n=220). A biomarker-enhanced risk score (KID-ACS score) for simultaneous prediction of in-hospital acute kidney injury (AKI) and 30-day mortality was derived and externally validated. Results On multivariable adjustment for established risk factors, circulating PENK remained associated with in-hospital AKI (per log2 increase: adjusted odds ratio [OR] 1.53, 95% confidence interval [CI] 1.13–2.09, P=0.007) and 30-day mortality (adjusted hazard ratio [HR] 2.73, 95% CI 1.85–4.02, P<0.001). The KID-ACS score integrates PENK and showed an area under the receiver operating characteristic curve (AUC) of 0.72 (95% CI 0.68–0.76) for in-hospital AKI, and of 0.91 (95% CI 0.87–0.95) for 30-day mortality in the derivation cohort. Upon external validation, KID-ACS achieved similarly high performance for in-hospital AKI (Zurich: AUC 0.73, 95% CI 0.70–0.77; Czechia: AUC 0.75, 95% CI 0.68–0.81; Germany: AUC 0.71, 95% CI 0.55–0.87) and 30-day mortality (UK: AUC 0.87, 95% CI 0.83–0.91; Czechia: AUC 0.91, 95% CI 0.87–0.94; Germany: AUC 0.96, 95% CI 0.92–1.00) outperforming the CA-AKI score and the GRACE 2.0 score, respectively. Conclusions Circulating PENK offers incremental value for predicting in-hospital AKI and mortality in ACS. The simple 6-item KID-ACS risk score integrates PENK and provides a novel tool for simultaneous assessment of renal and mortality risk in patients with ACS.

An overview of circulating and urinary biomarkers capable of predicting the transition of acute kidney injury to chronic kidney disease

Article

Full-text available

Jul 2024

Introduction: Acute kidney injury (AKI) defined by a substantial decrease in kidney function within hours to days and is often irreversible with higher risk to chronic kidney disease (CKD) transition. Areas covered: The authors discuss the diagnostic and predictive utilities of serum and urinary biomarkers on AKI and on the risk of AKI-to-CKD progression. The authors focus on the relevant literature covering evidence of circulating and urinary biomarkers’ capability to predict the transition of AKI to CKD. Expert opinion: Based on the different modalities of serum and urinary biomarkers, multiple biomarker panel seems to be potentially useful to distinguish between various types of AKI, to detect the severity and the risk of AKI progression, to predict the clinical outcome and evaluate response to the therapy. Serum/urinary neutrophil gelatinase-associated lipocalin (NGAL), serum/urinary uromodulin, serum extracellular high mobility group box-1 (HMGB-1), serum cystatin C and urinary liver-type fatty acid-binding protein (L-FABP) were the most effective in the prediction of AKI-to-CKD transition regardless of etiology and the presence of critical state in patients. The current clinical evidence on the risk assessments of AKI progression is mainly based on the utility of combination of functional, injury and stress biomarkers, mainly NGAL, L-FABP, HMGB-1 and cystatin C

Cardiorenal syndrome. Prognostic value of renal biomarkers. Literature review

Article

Full-text available

Jun 2024

cardiorenal syndrome includes a spectrum of disorders of the heart and kidneys, in which acute or chronic dysfunction of one organ can lead to the development of acute or chronic dysfunction of another organ. Changes in hemodynamics, activation of the renin-angiotensin-aldosterone system, metabolic disorders, inflammation, etc., are important in the pathogenesis of cardiorenal syndrome. The purpose of this article is to analyze and systematize the available contemporary scientific data on the role of renal biomarkers in stratifying the risk of development, mortality and repeated hospitalizations due to cardiorenal syndrome. Cardiorenal syndrome worsens the prognosis of patients, increases mortality, morbidity and the frequency of re-hospitalizations, therefore stratification of the risk of its development and early diagnosis are of great importance in order to timely prescribe treatment and improve the prognosis. Despite modern therapeutic treatment strategies, the mortality of patients with cardiorenal syndrome remains high. Serum creatinine still remains the "gold standard" for the diagnosis of kidney damage, although it is known as a low-sensitivity and unreliable biomarker, in particular, as is known, its concentration depends on gender, nutrition, muscle development, and tubular secretion. Taking into account these data, researchers and clinicians are making great efforts to find and study new biomarkers of acute kidney injury. Biomarkers of impaired function and integrity of kidney glomeruli include: serum creatinine, albuminuria, cystatin C, plasma proenkephalin A, galectin 3, and markers of impaired renal tubule integrity include: N-acetyl-beta-D-glucosaminidase, lipocalin, associated with neutrophil gelatinase, kidney damage molecule-1, etc. Literature data indicate that some of these new biomarkers are reliable predictors of the development of kidney damage and can be used to assess the prognosis of such patients.

Role of stanniocalcin-1 and proenkephalin-A as novel biomarkers in prediction of newly diagnosed type 2 diabetic patients

Article

May 2024

Diabetes mellitus is a chronic metabolic disorder that carries substantial implications for health, social well-being, and economic factors. Stanniocalcin-1 STC-1 is a polypeptide hormone that was initially distinguished as a controller of calcium/phosphate homeostasis in the fish. There is a growing evidence that human STC-1, an autocrine/paracrine factor, plays a role in both inflammation and carcinogenesis. The stable fragment proenkephalin-A (PENKA) is a novel biomarker derived from the precursor enkephalin, which is involved in multiple biological pathways. The objective of this study was to assess the significance of two newly discovered biomarkers, stanniocalcin-1 and proenkephalin-A, in patients recently diagnosed with type 2 diabetes. The study consisted of 90 participants, who were divided into two groups. The first group comprised 60 patients with recently diagnosed T2DM, while the second group consisted of 30 healthy individuals serving as controls. The age range of the participants spanned from 35 to 65 years. The study found a significant increase in body mass index (BMI), fasting blood glucose (FBG), HbA1c, C-peptide, HOMA-IR, total cholesterol (TC), triglyceride (TG), LDL, VLDL, stanniocalcin-1, and proenkephalin-A in patients with newly DM when compared with those in the control group. Also, there was a significant increase in HDL levels in the control group compared to the newly diagnosed diabetic group. In conclusion, the results of our study indicate that stanniocalcin-1 and proenkephalin-A could potentially be used as indicators of glucose homeostasis. Consequently, these biomarkers may offer an alternative to conventional markers in predicting risk factors for diabetes mellitus.

Point-of-Care Serum Proenkephalin as an Early Predictor of Mortality in Patients Presenting to the Emergency Department with Septic Shock

Article

Full-text available

May 2024

Background: The aim of the present study is to investigate the prognostic utility of point-of-care (POC)-measured proenkephalin (PENK), a novel biomarker, in terms of predicting in-hospital mortality in patients presenting to the emergency department (ED) with septic shock. Methods: Bedside PENK was measured in consecutive patients presenting to the ED with septic shock according to the Sepsis-3 clinical criteria. The association of PENK with inflammatory and routine biomarkers, and its role as a predictor of in-hospital mortality, was examined. Results: Sixty-one patients with septic shock [53% females, median age 83 years (IQR 71–88)] were evaluated. Median (IQR) values of creatinine, plasma lactate, soluble urokinase plasminogen activator receptor (SuPAR), procalcitonin and PENK were 1.7 (1.0–2.9) mg/dL, 3.6 (2.1–6.8) mmol/L, 13.1 (10.0–21.4) ng/mL, 2.06 (0.84–3.49) ng/mL, and 205 (129–425) pmol/L, respectively. LogPENK significantly correlated with LogLactate (rho = 0.369, p = 0.004), LogCreatinine (rho = 0.537, p < 0.001), LogProcalcitonin (rho = 0.557, p < 0.001), and LogSuPAR (rho = 0.327, p = 0.011). During hospitalization, 39/61 (64%) patients died. In a multivariable logistic regression model, logPENK was an independent predictor of in-hospital mortality (OR 11.9, 95% CI: 1.7–84.6, p = 0.013). Conclusion: POC PENK levels measured upon presentation to the ED strongly correlated with metabolic, renal and inflammatory biomarkers, and may serve as a predictor of in-hospital mortality in patients with septic shock.

Acute Kidney Injury in the Emergency Department: Role of Proenkephalin A 119-159

Article

Full-text available

Mar 2024

Plasma proenkephalin A and incident chronic kidney disease and albuminuria in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort

Article

Full-text available

Jan 2024
BMC Nephrol

Background Plasma proenkephalin A (PENK-A) is a precursor of active enkephalins. Higher blood concentrations have been associated with estimated glomerular filtration rate (eGFR) decline in European populations. Due to the significant disparity in incident chronic kidney disease (CKD) between White and Black people, we evaluated the association of PENK-A with incident CKD and other kidney outcomes among a biracial cohort in the U.S. Methods In a nested cohort of 4,400 participants among the REasons for Geographic And Racial Differences in Stroke, we determined the association between baseline PENK-A concentration and incident CKD using the creatinine-cystatin C CKD-EPI 2021 equation without race coefficient, significant eGFR decline, and incident albuminuria between baseline and a follow-up visit 9.4 years later. We tested for race and sex interactions. We used inverse probability sampling weights to account for the sampling design. Results At baseline, mean (SD) age was 64 (8) years, 49% were women, and 52% were Black participants. 8.5% developed CKD, 21% experienced ≥ 30% decline in eGFR and 18% developed albuminuria. There was no association between PENK-A and incident CKD and no difference by race or sex. However, higher PENK-A was associated with increased odds of progressive eGFR decline (OR: 1.12; 95% CI 1.00, 1.25). Higher PENK-A concentration was strongly associated with incident albuminuria among patients without diabetes mellitus (OR: 1.29; 95% CI 1.09, 1.53). Conclusion While PENK-A was not associated with incident CKD, its associations with progression of CKD and incident albuminuria, among patients without diabetes, suggest that it might be a useful tool in the evaluation of kidney disease among White and Black patients.

Biomarker Enrichment in Sepsis Associated Acute Kidney Injury: Finding High-Risk Patients in the ICU

Article

Oct 2023

Background: Sepsis associated Acute kidney injury (AKI) is a leading comorbidity in admissions to the intensive care unit. While a gold standard definition exists, it remains imperfect and does not allow for the timely identification of patients in the setting of critical illness. This review will discuss the use of biochemical and electronic biomarkers to allow for prognostic and predictive enrichment of patients with sepsis associated AKI over and above the use of serum creatinine and urine output. Summary: Current data suggest that several biomarkers are capable of identifying patients with sepsis at risk for the development of severe AKI and other associated morbidity. This review discusses this data and these biomarkers in the setting of sub-phenotyping and endotyping sepsis associated AKI. While not all of these tests are widely available and some require further validation, in the near future we anticipate several new tools to help nephrologists and other providers better care for patients with sepsis associated AKI. Key messages: Predictive and prognostic enrichment using both traditional biomarkers and novel biomarkers in the setting of sepsis can identify subsets of patients with either similar outcomes or similar pathophysiology respectively. Novel biomarkers can identify kidney injury in patients without consensus definition AKI (e.g. changes in creatinine or urine output); and can predict other adverse outcomes (e.g. severe consensus definition AKI, inpatient mortality). Finally, emerging artificial intelligence and machine learning derived risk models are able to predict sepsis associated AKI in critically ill patients using advanced learning techniques and several laboratory and vital sign measurements.

Assessment of Proenkephalin (PENK) and Interleukin-18 (IL-18) Biomarkers for Detection of Acute Kidney Injury in Patient with Acute Heart Failure

Article

Mar 2022

Acute kidney injury (AKI) is a reiterated kind of organ injury in acute heart failure (AHF). As for data collection, AKI markers of serum and urine were applied for both proenkephalin (S-PENK and U-PENK) and interlocune-18(S-IL-18 and U-IL-18) in AHF. The study aimed to evaluate the competency of (S-PENK and U-PENK) and (S-IL-18 and U-IL-18) to prognosticate acute kidney injury in AHF patients. Modern studies indicate that Proenkephalin (PENK) is produced in kidneys, muscles, lung, intestine, heart, and central nervous system. The cytokine interleukin-18 (IL-18) is involved in the detection of AKI in AHF patients. Serum and urine PENK and IL-18 levels for all healthy and AHF patients were tested via enzyme-linked immunosorbent assay (ELISA). The results notably revealed that serum PENK and urine PENK level increased considerably with disease severity and were quite compatible with those who reported higher mean serum PENK and urine PENK in patients diagnosed with AHF in comparison to the healthy control group. The results of this study suggest that S-PENK, U PENK, S-IL-18, and U-IL-18 can be useful potential biomarkers for diagnosis of AKI in patients AHF. In conclusion, the level of PENK and IL-18 is significantly increased in AHF, suggesting that PENK and IL-18 are a good indicator for detection of AKI in patients AHF.

30 Days Mortality Prognostic Value of POCT Bio-Adrenomedullin and Proenkephalin in Patients with Sepsis in the Emergency Department

Article

Full-text available

Dec 2022
MED LITH

Background and Objective: Sepsis is a worldwide severe disease with a high incidence and mortality rate. Sepsis is a frequent cause of admission to the emergency department (ED). Although prognostic scores (Sequential Organ Failure Assessment, SOFA; New Early Warning Score, NEWS; Rapid Emergency Medicine Score, REMS) are commonly used for risk stratification in septic patients, many of these scores are of poor utility in the ED. In this setting, biomarkers are promising alternatives, easier to perform and potentially more specific. Bio-adrenomedullin (Bio-ADM) and Proenkephalin (PenKid) seem to have a key role in the development of organ dysfunctions induced by sepsis and, therefore, could help in the risk stratification of patients with sepsis at ED admission. The aim of this study was to evaluate the utility of Bio-ADM and PenKid, obtained through a point of care (POCT) device, in predicting 30 days mortality for patients presenting to the ED with sepsis. Methods and Results: In total, 177 consecutive adult patients with a diagnosis of sepsis presenting to the ED of San Giovanni Addolorata Hospital in Rome, Italy, between May 2021 and April 2022 were enrolled in this prospective observational study. For each patient, Bio-ADM and PenKid were obtained at ED admission together with SOFA, NEWS and REMS scores. Next, 30 days follow-up data were collected to evaluate patient mortality. Both biomarkers (Bio-ADM and PenKid) and clinical scores (SOFA, NEWS and REMS) were good predictors of mortality at 30 days, with Bio-ADM and REMS outperforming the others. Moreover, PenKid resulted in being linked with the worsening of kidney function. Conclusions: In patients presenting with sepsis in the ED, Bio-ADM and PenKid, evaluated with a POCT device, predicted 30-day mortality. These two biomarkers seem even more useful when integrated with clinical risk scores at ED admission.

Proenkephalin A 119-159 predicts early and successful liberation from renal replacement therapy in critically ill patients with acute kidney injury: a post hoc analysis of the ELAIN trial

Article

Full-text available

Oct 2022

Background: Renal replacement therapy (RRT) remains the key rescue therapy for critically ill patients with severe acute kidney injury (AKI). However, there are currently no tools available to predict successful liberation from RRT. Biomarkers may allow for risk stratification and individualization of treatment strategies. Proenkephalin A 119-159 (penKid) has been suggested as a promising marker of kidney function in the context of AKI, but has not yet been evaluated for RRT liberation in critically ill patients with AKI. Methods: This post hoc analysis included 210 patients from the randomized clinical ELAIN trial and penKid levels were measured in the blood of these patients. Competing risk time-to-event analyses were performed for pre-RRT penKid at initiation of RRT and in a landmark analysis at day 3 after initiation of RRT. Competing risk endpoints were successful liberation from RRT or death without prior liberation from RRT. Results: Low pre-RRT penKid levels (penKid ≤ 89 pmol/l) at RRT initiation were associated with early and successful liberation from RRT compared to patients with high pre-RRT penKid levels (subdistribution hazard ratio (sHR) 1.83, 95%CI 1.26-2.67, p = 0.002, estimated 28d-cumulative incidence function (28d-CIF) of successful liberation from RRT 61% vs. 45%, p = 0.022). This association persisted in the landmark analysis on day 3 of RRT (sHR 1.78, 95%CI 1.17-2.71, p = 0.007, 28d-CIF of successful liberation from RRT 67% vs. 47%, p = 0.018). For both time points, no difference in the competing event of death was detected. Conclusions: In critically ill patients with RRT-dependent AKI, plasma penKid appears to be a useful biomarker for the prediction of shorter duration and successful liberation from RRT and may allow an individualized approach to guide strategies of RRT liberation in critically ill patients with RRT-dependent AKI. Trial registration: The ELAIN trial was prospectively registered at the German Clinical Trial Registry (Identifier: DRKS00004367) on 28th of May 2013.

Proenkephalin A as a marker for glomerular filtration rate in critically ill children: validation against gold standard iohexol GFR measurements

Article

Full-text available

Oct 2022
CLIN CHEM LAB MED

Objectives Accurate determination of glomerular filtration rate (GFR) is important. Several endogenous biomarkers exist for estimating GFR, yet, they have limited accuracy, especially in the paediatric population. Proenkephalin A 119–159 (PENK) is a novel and promising GFR marker, but its relation with age in children remains unknown. Also, the value of PENK has never been validated against measured GFR (mGFR) in children when compared to traditional GFR markers including serum creatinine (SCr), SCr-based estimated GFR (eGFR) and cystatin C (cysC). Methods Critically ill children and term-born neonates were included in this single-centre, prospective study. Iohexol-based mGFR, SCr, and cysC were determined in each patient. eGFR was calculated using the bedside Schwartz equation, incorporating SCr and height. Spearman correlation coefficients were calculated to determine the correlation between mGFR and PENK, SCr, cysC and eGFR. Results For 97 patients (56 children and 41 neonates), mGFR, SCr, cysC and PENK levels were available. PENK levels were higher in young children and decreased to adult PENK reference values around two years of age. PENK levels were highly correlated with mGFR (ρ=−0.88, p<0.001), and similar to mGFR–eGFR correlation (ρ=−0.87, p<0.001). For cysC and SCr the correlation with mGFR was lower (ρ=−0.77 and ρ=−0.46, respectively. Both p<0.001). Conclusions The correlation of PENK with mGFR was as good as SCr-based eGFR-mGFR correlation. To determine the added value of PENK in paediatric clinical care and prior to implementation, PENK reference values are needed and the development and validation of a paediatric PENK-based eGFR equation is necessary.

Proenkephalin A119-159 As A Biomarker of Acute Kidney Injury in ICU Patients with Sepsis

Article

Full-text available

Oct 2022

Potential Long-Term Health Problems Associated with Ultra-Endurance Running: A Narrative Review

Article

Full-text available

Apr 2022
SPORTS MED

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.

Biomarkers of acute kidney injury and their role in clinical patient management

Article

Full-text available

May 2020

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.

Biomarkers in Acute Kidney Injury

Article

Apr 2021
CRIT CARE CLIN

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.

Predictive value of plasma proenkephalin and neutrophil gelatinase-associated lipocalin in acute kidney injury and mortality in cardiogenic shock

Article

Full-text available

Feb 2021

Abstract 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 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 105.7 pmol/L and P-NGAL24h > 151 ng/mL had unadjusted hazard ratios of 5.6 (95% CI 3.1–10.7, p

A call to action to evaluate renal functional reserve in COVID-19 patients

Article

Sep 2020
AM J PHYSIOL-RENAL

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.

Biomarker-Guided Risk Assessment for Acute Kidney Injury: Time for Clinical Implementation?

Article

Full-text available

Jan 2021
ANN LAB MED

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.

Proenkephalin Predicts Organ Failure, Renal Replacement Therapy, and Mortality in Patients With Sepsis

Article

Full-text available

Nov 2020
ANN LAB MED

Background: Kidney failure occurs frequently and is associated with high mortality during sepsis. Proenkephalin (PENK) is an emerging biomarker of kidney function. We explored whether PENK levels could predict severity, organ failure, and mortality in septic patients. Methods: We measured the PENK level in the plasma of 215 septic patients using the sphingotest penKid assay (Sphingotec GmbH, Hennigsdorf, Germany). This was analyzed in terms of sepsis severity, vasopressor use, 30-day mortality, sequential organ failure assessment (SOFA) renal subscore, the Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (CKD-EPI eGFR) categories, and renal replacement therapy (RRT) requirement. Results: The PENK levels were significantly higher in patients with septic shock, vasopressor use, and non-survivors than in patients with solitary sepsis, no vasopressor use, and survivors, respectively (P=0.02, P=0.007, P<0.001, respectively). The PENK levels were significantly associated with SOFA renal subscore and CKD-EPI eGFR categories (both P<0.001). The distribution of lower eGFR (<60 mL/min/1.73 m2), RRT requirement, SOFA renal subscore, and the number of organ failures differed significantly according to the PENK quartile (P for trend<0.001 or 0.017). The 30-day mortality rate also differed significantly according to the PENK quartile (P for trend<0.001). Conclusions: PENK could be an objective and reliable marker to predict severity, organ failure, and 30-day mortality in septic patients.

Proenkephalin, an Opioid System Surrogate, as a Novel Comprehensive Renal Marker in Heart Failure

Article

May 2019

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.

Renal elimination and eGFR prediction of proenkephalin

Article

Jun 2025
SCAND J CLIN LAB INV

Proenkephalin (PENK): a functional biomarker in chronic kidney diseases – hope or just a new bystander?

Article

Apr 2025
J NEPHROL

Proenkephalin has recently emerged as a promising biomarker of kidney function which improves the early detection of acute kidney injury (AKI) compared to creatinine-based methods. Plasma Proenkephalin concentrations have shown a correlation with glomerular filtration rate (GFR) as assessed by gold standard methods. Previous studies have demonstrated its association with adverse clinical outcomes in various settings, including sepsis, heart failure, kidney transplantation, and chronic kidney disease (CKD). Additionally, in healthy individuals, elevated Proenkephalin concentrations have been linked to a decline in GFR and an increased risk of developing CKD. While evidence suggests that Proenkephalin may be a more accurate tool for assessing glomerular filtration and detecting AKI, recent research has primarily focused on subjects with preserved kidney function, leaving its value in CKD patients less explored. Given the heterogeneity and high risk of rapid renal deterioration in patients with chronically impaired kidney function, a reliable biomarker should retain its ability to reflect kidney function in both CKD and AKI settings. This review summarizes the current evidence on Proenkephalin in patients with chronic kidney diseases.

Current and novel biomarkers in cardiogenic shock

Article

Jan 2025
EUR J HEART FAIL

Cardiogenic shock (CS) carries a 30–50% in‐hospital mortality rate, with little improvement in outcomes in the last decade. Challenges in improving outcomes are closely linked to the frequent late presentation or diagnosis of CS where the ‘point of no return’ has often passed, leading to haemodynamic dysregulation, progressive myocardial depression, hypotension, and a downward spiral of hypoperfusion, organ dysfunction and decreasing myocardial function, driven by inflammation and metabolic derangements. Novel therapeutic interventions may have varying efficacy depending on the type and stage of shock in which they are applied. Biomarkers that aid prediction and early detection of CS, provide early signs of organ dysfunction and define prognosis could help optimize management. Temporal change in such biomarkers, particularly in response to pharmacological interventions and/or mechanical circulatory support, can guide management and predict outcome. Several novel biomarkers enhance the prediction of mortality in CS, compared to conventional parameters such as lactate, with some, such as adrenomedullin and circulating dipeptidyl peptidase 3, also able to predict the development of CS. Some biomarkers reflect systemic inflammation (e.g. interleukin‐6, angiopoietin 2, fibroblast growth factor 23 and suppressor of tumorigenicity 2) and are not specific to CS, yet inform on the activation of important pathways involved in the downward shock spiral. Other biomarkers signal end‐organ hypoperfusion and could guide targeted interventions, while some may serve as novel therapeutic targets. We critically review current and novel biomarkers that guide prediction, detection, and prognostication in CS. Future use of biomarkers may help improve management in these high‐risk patients.

Human Proenkephalin A 119-159 (PenKid) in extracorporeal therapies: Ex-Vivo Sieving Coefficient, Diffusive Clearance and Hemoadsorption Kinetics

Article

Jul 2024

Introduction: Enkephalins, endogenous opioid peptides, are involved in the regulation of renal function. One derived molecule, proenkephalin A, also known as penKid, has been demonstrated to be a reliable biomarker for kidney function and its plasma concentration correlates with measured glomerular filtration rate. penKid is used for prediction and diagnosis of AKI and need of renal replacement therapy (RRT). penKid has also been used to predict the successful weaning from RRT in patients with AKI. Whether the concentration of penKid is affected or not by RRT is a controversial point and there are no studies describing the kinetics of the molecule in such conditions. The low molecular weight (4.5 kDa) would imply free removal by the glomerulus and the dialysis membranes. During RRT, this reduction could not be detected in clinical practice due to the complex kinetics involving either low dialytic clearance or increased production in response to impaired kidney function. The aim of this study was to determine the sieving coefficient and the diffusive clearance of the penKid molecule in conditions of in vitro continuous veno-venous hemofiltration (CVVH) and continuous veno-venous hemodialysis (CVVHD), respectively, and also the penKid removal ratio in conditions of in vitro hemoadsorption (HA) using a synthetic microporous resin. Methods: Blood spiked with a lyophilized penKid peptide solved in 20 m m dipotassium phosphate and 6 m m disodium EDTA [pH 8] to reach target concentrations is used as testing solution. In each experiment, the blood batch was adjusted at a volume of 1,000 mL, maintained at 37°, and continuously stirred. Samples were collected from blood, ultrafiltrate, and spent dialysate at different times during the experiments. Sieving, clearance, and removal ratio were calculated. Results: Significant removal of penKid was observed in CVVH (sieving 1.04 ± 0.27), in CVVHD (clearance 23.08 ± 0.89), and in HA (removal ratio 76.1 ± 1% after 120 min). Conclusion: penKid is effectively removed by extracorporeal therapies. In presence of anuria, penKid generation kinetics can be calculated based on extracorporeal removal and volume variation. In steady state conditions, declining values may be the result of an initial renal function recovery and may suggest discontinuation and successful liberation from RRT.

NephroPOC – Proenkephalin A 119-159 predicts acute kidney injury and 28-day mortality in patients with suspected organ dysfunction in the emergency department (ED): secondary analysis from the prospective observational LifePOC study

Preprint

Full-text available

Jan 2024

Background: Volume depletion, sepsis, major surgery, and nephrotoxins are the most common causes of acute kidney injury (AKI). The classical markers serum creatinine (Scr) and urine output (UO) for the evaluation of kidney function are of limited value in critical ill patients because they reflect an already existing organ dysfunction. Our hypothesis is that the measurement of the functional biomarker Proenkephalin A 119-159 (penKid), which is freely filtered in the glomerulus and is used as a marker for estimating the glomerular filtration rate, contributes to the early identification of patients with subclinical kidney damage. Methods: This was a secondary analysis of the prospective multicenter LifePOC study. We evaluated critically ill patients admitted to the emergency department (ED) with suspected organ dysfunction based on the risk-stratification tool qSOFA , who developed AKI, defined as Scr ≥0.3 mg/dl from baseline, within 72 hours of enrolment. The primary endpoint was evolving AKI after 48 h. AKI after 24 h, AKI after 72 h and 28-day mortality were defined as secondary endpoints. Measurement and main results: Within 48 h, 88 out of 453 patients (19.4%) developed AKI. Patients with AKI showed increased penKid levels at admission in comparison to patients without AKI (111.5 [73.0-247.5] pmol/l vs. 74.8 [47.2-120.4] pmol/l, p<0.001). PenKid was a superior predictor for AKI within 24, 48 and 72 h in comparison to Scr (all p<0.05), and the advantage increased the later the renal events occurred. Regarding 28-day mortality prediction, penKid also outperformed Scr (p<0.05). The observed superiority of penKid persisted if the recently proposed PENK-Crea formula to estimate the GFR was applied and compared to the latest CKD-EPI formula. Conclusions: Early measurement and the trajectory of penKid predicts early AKI and 28-day mortality in patients with suspected organ dysfunction in the ED superior compared to the classical marker Scr. The results indicate that the superiority is attributed to an earlier rise in penKid compared to Scr. Trial registration: The trial was registered in the German Registry for Clinical Trials (DRKS00011188) on 20 October 2016.

The role of Proenkephalin A 119–159 in the detection of acute kidney injury after open thoracoabdominal aortic repair

Article

Nov 2023
Vasa

Background: Acute kidney injury (AKI) after open thoracoabdominal aortic aneurysm repairs (TAAA) is a common postoperative complication, associated with increased mortality and morbidity. Early detection and management of the kidney tissue damage remains of paramount importance. The aim of this prospectively conducted, observational trial was to evaluate the clinical applicability of Proenkephalin A 119–159 (penKid) for the detection of postoperative AKI. Patients and methods: Thirty-six patients, planned for elective open TAAA repairs from January 2019 to December 2022, were recruited in two German centres (University Hospital Aachen and Charité – University Hospital Berlin). Blood samples were collected pre-surgery (baseline), directly postoperatively and at 12, 24 and 48 hours after surgery. The penKid concentration in plasma was measured using the immunoluminometric sphingotest® assay kit and they were statistically tested for association with AKI and other clinical parameters. Results: Twenty-four patients (62%) developed moderate or severe AKI postoperatively (Stage 2 or 3 of the KDIGO classification) and they had a significantly increased risk for the development of acute respiratory distress syndrome (p=.023) or a fatal outcome (p=.035). Starting from the 12th hour after surgery, we found penKid correlating with AKI stage 2/3 (12 hour penKid mean in pmol/L: 93.9 vs. 43.1; c index .776, p=.0037) and renal replacement therapy (12 hour c index .779, p=.0035). Patients with multi-organ dysfunction syndrome had significantly increased penKid levels at all timepoints. Conclusions: We found penKid to be a promising biomarker for the early detection of postoperative AKI and in-hospital mortality after open TAAA repair, which may enable the early initiation of organ-protective strategies and reduction of further complications associated with AKI.

Assessing Glomerular Filtration Rate with Proenkephalin

Article

Aug 2023

Introduction In clinical practice, kidney (dys)function is monitored through creatinine-based estimations of glomerular filtration rate (eGFR: Modification of Diet in Renal Disease [MDRD], Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]). Creatinine is recognized as a late and insensitive biomarker of glomerular filtration rate (GFR). The novel biomarker proenkephalin (PENK) may overcome these limitations, but no PENK-based equation for eGFR is currently available. Therefore, we developed and validated a PENK-based equation to assess GFR. Methods In this international multicenter study in 1354 stable and critically ill patients, GFR was measured (mGFR) through iohexol or iothalamate clearance. A generalized linear model with sigmoidal nonlinear transfer function was used for equation development in the block-randomized development set. Covariates were selected in a data-driven fashion. The novel equation was assessed for bias, precision (mean ± SD), and accuracy (eGFR percentage within ±30% of mGFR, P30) in the validation set and compared with MDRD and CKD-EPI. Results Median mGFR was 61 [44–81] ml/min per 1.73 m². In order of importance, PENK, creatinine, and age were included, and sex or race did not improve performance. The PENK-based equation mean ± SD bias of the mGFR was 0.5 ± 15 ml/min per 1.73 m², significantly less compared with MDRD (8 ± 17, P < 0.001) and 2009 CKD-EPI (5 ± 17, P < 0.001), not reaching statistical significance compared with 2021 CKD-EPI (1.3 ± 16, P = 0.06). The P30 accuracy of the PENK-based equation was 83%, significantly higher compared with MDRD (68%, P < 0.001) and 2009 CKD-EPI (76%, P < 0.001), similar to 2021 CKD-EPI (80%, P = 0.13). Conclusion Overall, the PENK-based equation to assess eGFR performed better than most creatinine-based equations without using sex or race.

Proenkephalin A 119–159 (penKid) – a novel biomarker and its quantification on the Nexus IB10 POC system for assessing kidney function

Article

Jan 2023

Insuffisance rénale aiguë : rôle du métabolisme, place du facteur de transcription HNF-1b et identification de nouveaux biomarqueurs diagnostiques

Thesis

Oct 2021

Alexis Piedrafita

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.

Reflections on the KDIGO Definition of Acute Kidney Injury and Its Integration in the Concept of Acute Diseases and Disorders and Chronic Kidney Diseases

Article

Full-text available

Feb 2022

Norbert Lameire

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.

Plasma Pro-Enkephalin A and Ischemic Stroke Risk: The Reasons for Geographic and Racial Differences in Stroke Cohort

Article

Feb 2022
J Stroke Cerebrovasc Dis

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.

Construction of circRNA-miRNA-mRNA network in the pathogenesis of recurrent implantation failure using integrated bioinformatics study

Article

Full-text available

May 2021
J CELL MOL MED

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.

The effects of physical exercise on the assessment of kidney function

Article

May 2020

Biomarkers of Infection: Are They Useful in the ICU?

Article

Aug 2019

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.

Proenkephalin, Neutrophil Gelatinase-Associated Lipocalin, and Estimated Glomerular Filtration Rates in Patients With Sepsis

Article

Full-text available

Sep 2017

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.

Acute kidney injury in the ICU: from injury to recovery: reports from the 5th Paris International Conference

Article

Full-text available

Dec 2017

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

Sequential Analysis of a Panel of Biomarkers and Pathologic Findings in a Resuscitated Rat Model of Sepsis and Recovery

Article

Full-text available

Apr 2017
CRIT CARE MED

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.

Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study

Article

Full-text available

Jul 2015
INTENS CARE MED

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.

Assessment of Cell-Cycle Arrest Biomarkers to Predict Early and Delayed Acute Kidney Injury

Article

Full-text available

Mar 2015
DIS MARKERS

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.

Quantification of urinary TIMP-2 and IGFBP-7: An adequate diagnostic test to predict acute kidney injury after cardiac surgery?

Article

Full-text available

Jan 2015

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.

Proenkephalin predicts acute kidney injury in cardiac surgery patients

Article

Full-text available

Jan 2015
CLIN NEPHROL

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.

Diagnostic and short-term prognostic utility of plasma pro-enkephalin (pro-ENK) for acute kidney injury in patients admitted with sepsis in the emergency department

Article

Full-text available

Dec 2014

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

The rise and fall of NGAL in acute kidney injury

Article

Full-text available

Aug 2014

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.

Clinical review: Predictive value of neutrophil gelatinase-associated lipocalin for acute kidney injury in intensive care patients

Article

Full-text available

Apr 2013

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.

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Article

Full-text available

Feb 2013

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.

The severity of acute kidney injury predicts profession to chronic kidney disease.

Article

Full-text available

Mar 2011
KIDNEY INT

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.

Limitations of Creatinine as a Filtration Marker in Glomerulopathic Patients

Article

May 1986

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.

Proenkephalin, Renal Dysfunction, and Prognosis in Patients With Acute Heart Failure. A GREAT Network Study

Article

Jan 2017
J AM COLL CARDIOL

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.

Clinical Correlates and Prognostic Value of Pro-Enkephalin in Acute and Chronic Heart Failure

Article

Sep 2016

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.

Biomarkers in acute kidney injury - pathophysiological basis and clinical performance

Article

Jul 2016
ACTA PHYSIOL

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 Level of Fasting Plasma Proenkephalin-A Predicts Deterioration of Kidney Function and Incidence of CKD

Article

Jul 2016

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.

Prognostic Usefulness of Proenkephalin in Stable Ambulatory Patients With Heart Failure

Article

Feb 2016

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.

A More Accurate Method To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation

Article

Mar 1999

Andrew S. Levey

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.

A New Equation to Estimate Glomerular Filtration Rate

Article

May 2009

Andrew S. Levey

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.

Proenkephalin and Prognosis After Acute Myocardial Infarction

Article

Oct 2013

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.

Acute kidney injury: An increasing global concern

Article

May 2013
LANCET

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.

Demystifying ethnic/sex differences in kidney function: Is the difference in (estimating) glomerular filtration rate or in serum creatinine concentration?

Article

May 2012

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.

Estimating GFR using the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, and better risk predictions

Article

Apr 2010
AM J KIDNEY DIS

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

Measured GFR as a confirmatory test for estimated GFR

Article

Nov 2009
J AM SOC NEPHROL

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.

A New Equation to Estimate Glomerular Filtration Rate

Article

May 2009
ANN INTERN MED

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.

Reduced Production of Creatinine Limits Its Use as Marker of Kidney Injury in Sepsis

Article

May 2009
J AM SOC NEPHROL

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.

Identification of two related pentapeptides from the brain with potent opiate agonist activity

Article

Jan 1976

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.

Translation of heart preproenkephalin mRNA and secretion of enkephalin peptides from cultured cardiac myocytes

Article

Dec 1992
Am J Physiol

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.

The Diuretic and Antidiuretic Effect of Morphine Sulphate in Rats

Article

May 1970

Claude Marchand

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.

Inhibition of release in man by an opiate peptide

Article

Dec 1980

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 on circulating met-enkephalin and β-endorphin: Normal subjects and patients with renal and adrenal disease

Article

Oct 1981

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.

Precision of Glomerular Filtration Rate Determinations for Long-Term Slope Calculations is Improved by Simultaneous Infusion of 125I-Iothalamate and 131I-Hippuran

Article

Apr 1996

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.

Opioid mechanisms controlling renal function

Article

Jan 1996

Daniel Kapusta

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.

Renal Excretory Responses Produced by the Delta Opioid Agonist, BW373U86, in Conscious Rats

Article

Nov 1998

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.

A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group

Article

Apr 1999

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.

How to assess glomerular function and damage in humans

Article

Apr 1999

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.

Peptide repertoire of human cerebrospinal fluid: Novel proteolytic fragments of neuroendocrine proteins

Article

May 2001
J Chrom B Biomed Sci Appl

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.

Endogenous Cardiac Opioids: Enkephalins in Adaptation and Protection of the Heart

Article

Feb 2003

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.

Proenkephalin A 119-159, a stable proenkephalin A precursor fragment identified in human circulation

Article

Aug 2006
PEPTIDES

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.

The renal excretion of endogenous creatinine in man. Comparison with exogenous creatinine and inulin

Article

Feb 1938

Proenkephalin expression and enkephalin release are widely observed in non-neuronal tissues

Article

Feb 2008
PEPTIDES

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 in the United States: the Third National Health and Nutrition Examination Survey (NHANES III)

Article

Mar 2008
AM J KIDNEY DIS

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.

Jan 2017
49

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

Jan 2017

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

Jan 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

Jan 2017
J CARD FAIL
231-239

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

Jan 2017

E Peters

Peters E. Plasma penkid to monitor kidney function following cardiac surgery [abstract] in AKI & CRRT 2017. San Diego (CA); 2017.

Limitations of creatinine as a filtration marker in glomerulopathic patients

Jan 1985
830

Shemesh

Proenkephalin (PENK) as a Novel Biomarker for Kidney Function

Abstract

No full-text available

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Proenkephalin: A New Biomarker for Glomerular Filtration Rate and Acute Kidney Injury