Proenkephalin A 119-159
(penKid)
The kidney function biomarker
The current biomarkers used in the critical care routine to detect acute kidney injury (AKI) include serum creatinine and urine output. The inherent limitations of these biomarkers such as delayed detection of kidney deterioration and error proneness, urge the need for novel biomarkers. An emerging body of evidence demonstrates that the biomarker Proenkephalin A 119-159 (penKid*) overcomes these limitations.
Current blind spots of routinely used biomarkers:
- AKI is mostly symptom-free in the early disease stages.
- Current biomarkers show delayed recognition when 50% of kidney function is already lost.
- Standard biomarkers require observation at least at two independent time points.
- Comorbidities, personal factors (e.g. age and muscle mass) and treatments influence currently used biomarkers.
Potential advantages of the kidney function biomarker penKid:
- Showing kidney function in real-time (1).
- Predicting the incidence of AKI within 48h in septic patients (2,3).
- Correlating with the in vivo measurement of glomerular filtration rate (GFR) (4,5,6).
- Reflecting kidney function in adults (7,8,9) and children, representing a biomarker for pediatric AKI (10).
- Independent of inflammation (1,2,3,11) and common comorbidities, e.g. diabetes (2).
The biomarker penKid is convincing in clinical reseach
True GFR representation
PenKid is a blood-based parameter that strongly correlates with true GFR (5,7).
Kidney function in real-time
Monitoring penKid identification of patients with developing AKI (4,5,6,12).
Monitoring patient severity
Relative changes in penKid blood concentration show the improvement or deterioration of kidney function (3,5,6,8).
Applicable in critical conditions
PenKid is independent of inflammation (1,2,3,11) or common comorbidities, e.g. diabetes (2).
scientific evidence
A small molecule becomes a messenger for a serious disease
The best indicator of kidney function is the glomerular filtration rate (GFR) (5,7). However, the gold standard technique for determining the actual GFR relies on complex, time-consuming, expensive intervention using injected tracer substances such as inulin or iothalamate, which is not feasible in daily practice (13). Clinical routine relies on determining an estimated GFR (eGFR) using formulas which have been derived from patients with chronic and stable conditions (14). However, a plethora of non-renal factors (muscle mass, inflammation, among others) influence serum creatinine and thereby the result.
An emerging body of evidence demonstrates that monitoring penKid levels, which is exclusively eliminated through the kidney (43) and thereby reflects the true GFR, overcomes these limitations (4,5,6). PenKid levels reveal kidney function in real-time and offer a blood-based alternative for the complex and time-consuming in vivo measurement of true GFR.
Healthy state
Kidney function is stimulated by the hormone Enkephalin (15) which itself is difficult to detect due to its instability. During enkephalin processing, the stable fragment Proenkephalin A 119-159 (penKid) is generated. Quantification of penKid overcomes this analytical limitation and enables indirect assessment of kidney function.
Disease state
The administration of nephrotoxic drugs or critical illness can lead to an impairment of kidney function, which may increase enkephalin production to stimulate renal function, by increasing urine flow and sodium excretion (15). The kidney status can thus be indirectly assessed by measuring penKid blood levels, which reflects kidney function in real-time and remains independent of inflammation (1,2,3,11) and common comorbidities (2).
Monitoring kidney function in real-time using the biomarker penKid
SCIENTIFIC EVIDENCE
Independent of common comorbidities (e.g. diabetes) and the frequently occurring systemic inflammation in critically ill patients, rising penKid blood levels [1] predict acute kidney injury up to 48 hours earlier than today’s standard of care (16). Importantly, decreasing penKid blood levels [2] as a consequence of early resuscitation indicates the improvement of kidney function (2).
| Pooled sensitivity | 0.69 (95% CI 0.62-0.75) |
|---|---|
| Pooled specificity | 0.76 (95% CI 0.68-0.82) |
| Positive likelihood ratio | 2.83 (95% CI 2.06-3.88) |
| Negative likelihood ratio | 0.41 (95% CI 0.33-0.52) |
| Area under the curve | 0.77 (95% CI 0.73-0.81) |
Table 1: Pooled performance criteria of penKid for early detection of AKI. Results from a systematic review with meta-analysis incorporating 11 observational studies with 3,969 patients and 23.4% AKI incidence (33).
Clinical research
Sepsis and septic shock
Intensive care units (ICU): Critically ill patients with sepsis or septic shock admitted to the ICU require efficient diagnostic strategies to predict acute kidney deterioration and enable monitoring of recovery of renal function. PenKid predicted major adverse kidney events, transient AKI, worsening of renal function, and renal recovery in ICU patients (2,3).
Clinical performance characteristics: 529 adult patients with sepsis or septic shock and available AKI diagnoses were enrolled in a clinical performance study (34). Performance was calculated for identification of patients with an increase of serum creatinine (in respect to admission baseline values) within 48 hours after enrolment in the study.
Heart failure
In heart failure, elevated penKid levels provide important prognostic information across the disease spectrum. In acute heart failure (AHF), particularly in patients with renal dysfunction and inadequate decongestion during hospitalization, a rapid increase in penKid helps identify individuals who do not tolerate intensified diuretic therapy and predicts worsening renal function, rehospitalization, in-hospital and long-term mortality (9,18,19,20, 35, 36). In chronic heart failure (CHF), especially in heart failure with preserved ejection fraction (HFpEF), where effective monitoring biomarkers are lacking, high penKid levels have been associated with heart failure rehospitalization (21) and recurrence of acute myocardial infarction (22). Furthermore, in stable ambulatory patients with heart failure, increased penKid levels demonstrate significant predictive value for risk stratification (23), supporting early identification of patients at risk of organ failure and poor outcomes.
Kidney transplantation
PenKid is associated with kidney function in renal transplant recipients (RTR) and in healthy kidney donors (27). A common complication after kidney transplantation is delayed graft function (DGF) (37). PenKid provides a significant clinical advantage by identifying patients at risk for DGF well before traditional biomarkers like serum creatinine show any changes (38). Moreover, penKid distinguishes between slow- and delayed graft function with remarkable accuracy, up to eight days earlier than conventional assessment (38). Furthermore, increased penKid levels are associated with an elevated risk of long-term graft failure (27).
Renal replacement therapy
Critically ill patients are often at risk of developing AKI and are likely in need of organ support, such as kidney replacement therapy (KRT) (30). The monitoring of kidney function under KRT is crucial to guide successful discontinuation of therapy. However, current clinical practice, which– besides clinical characteristics – heavily relies on urine output, requires improvement for an informed decision-making to discontinue KRT. Plasma concentrations of penKid are maintained under KRT (39), making penKid a valuable tool for monitoring patients under KRT and for guiding KRT discontinuation. Recent data has shown that penKid levels at CKRT discontinuation discriminate between patients successfully and unsuccessfully liberated from CKRT (40).
Pediatric ICU
Pediatric AKI is often diagnosed too late for successful therapeutic interventions, leading to adverse outcomes and chronic kidney impairment (41). PenKid identifies AKI and its severity in critically ill neonates and children under one year of age, offering a potential solution to the shortcomings in pediatric critical care (10,42).
PenKid Whitepaper
The whitepaper covers practical insights on the AKI diagnostics and highlights the scientific evidence for penKid, a kidney function biomarker.
*Disclaimer
ELISA sphingotest® penKid®, sphingotest® penKid®, and sphingotest® bio-ADM® are offered for research use only. “penKid” and “bio-ADM” represent the analytes Proenkephalin A 119-159 and bioactive Adrenomedullin 1-52, respectively.
Reference Literature
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