Markers Cardio-renali

A DBrain natriuretic peptide (BNP)

Both BNP and NT-proBNP levels in the blood are used for screening, diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure, as both markers are typically higher in patients with worse outcome.

The plasma concentrations of both BNP and NT-proBNP are also typically increased in patients with asymptomatic or symptomatic left ventricular dysfunction.

There is no level of BNP that perfectly separates patients with and without heart failure.

BNP: albero decisionale

Paziente con dispnea

Esame obiettivo, Rx torace, ECG

livelli di BNP

BNP <100 pg/mL BNP 100-500 pg/mL BNP >500 pg/mL

HF molto improbabile Sospetto clinico di HF o HF molto probabile(2%) storia pregressa di HF? (90%)

HF probabile (90%)

Valore soglia di BNP raccomandato 100 pg/mL

Biomarkers: AMI versus AKI

AKI: A Common, Serious Problem

AKI is present in 5% of all hospitalized patients, and up to 30% of patients in Intensive Care

• The incidence is increasing at an alarming rate
• Mortality rate >50% in dialyzed ICU patients
• 25% of ICU dialysis survivors progress to end stage renal disease within 3 yrs
• % of all “ discharged dead”” with a diagnosis of ARFdead

pathogenic processes, or pharmacological responses to a therapeutic intervention

Type 0 biomarker

• A marker of the natural history of a disease that correlates longitudinally with known clinical indices

Type 1 biomarker

• A marker that captures the effects of a therapeutic intervention in accordance with its mechanism of action

Surrogate end point (type 2 biomarker)

• A marker that is intended to substitute for a clinical end point (i.e. s-Creat doubling); a surrogate end point is expected to predict clinical benefit (or harm or lack of benefit) on the basis of epidemiological, therapeutic, pathophysiologic, or other scientific evidence

Biomarkers Definitions Working Group, NIH, 2001

Clin Pharmacol Ther

Biomarkers: AMI versus AKI

Acute Kidney Injury

Acute Myocardial Infarction

Period Serum creatinine

1960s LDH Serum creatinine

1970s CPK, myoglobin Serum creatinine

1980s CK - MBCK-MB Serum creatinine

1990s Troponin T Serum creatinine

2000s Troponin I

Multiple Therapies Supportive Care

50%

↓ Mortality High Mortality

Diagnosis of AKI is often delayed!

Which is the need for biomarkers in AKI?

• Elevation in serum creatinine is the current gold standard, but this is problematic
• Normal serum creatinine varies widely with age, gender, diet, muscle mass, muscle metabolism, medications, and hydration status
• In AKI, serum creatinine can take several days to reach a new steady state
• Up to 50% of kidney function may be lost before serum creatinine even begins to rise

Diagnosis of AKI is often delayed!

Which Role for Biomarkers in AKI?

• Early prediction and diagnosis of AKI (before increase in serum creatinine)
• Identify the primary location of injury (proximal tubule, distal tubule, interstitium, vasculature)
• Pick out the duration (Prerenal, AKI, CKD) and severity
• Identify the etiology of AKI (ischemic, septic, toxic, combination)
• Differentiate from other types of kidney disease (UTI, GN, IN)
• Predict the outcome (need for RRT, length of)

9 Monitor response to intervention and treatment

9 Critical Path to Expedite the drug development process New Medical Products, FDA 2004

Ideal Biomarker in AKI assessment at bedside

1. Noninvasive and easy to perform at the bedside or in a standard clinical laboratory, using easily accessible samples such as blood or urine
2. Rapidly and reliably measurable using a standardized assay platform (i.e. ELISA)
3. Highly sensitive to facilitate early detection with a wide dynamic range and cut-off values (risk stratification)

Biomarkers: From Bench To Bedside

Specificity, ROC

• Use biomarker to screen population

Phase 4 Prospective Screening

• Identify extent and characteristics of disease

• Identify false referral rate

• Determine impact of screening on reducing

Phase 5 Disease Control

• disease burden

Modified from Pepe MS et al, 2001J Natl Cancer Inst

“Storici” Biomarker Urinari di Danno Renale

Netti GS et al, 2008G Ital Nefrol

NGAL

• Neutrophil Elastase-Associated Lipocalin

• First identified as a neutrophil granule protein

• Normally very small amounts in kidney tubules

• The most upregulated gene in the kidney by gene chip analysis, very early after ischemic or nephrotoxic AKI in animals

NGAL before … … and after 30min ischemia … Mouse Ischemia (30 min)

• S creat ↑ 24 h

• Kidney NGAL ↑ 3 h

• Colocalize with PCNA

• (proliferating cell nuclear antigen)

NGAL/PCNA

Mishra J et al, 2003; Mishra J et al, 2004J Am Soc Nephrol. J Am Soc Nephrol.

NGAL

acts as an acute phase protein which is rapidly released upon kidney injury

• Human adults in ICUs with ARF (sepsis, ischemia, or nephrotoxins) displayed >10-fold increase in plasma NGAL and >100-fold increase in urine NGAL, when compared with normal controls (Intense cortical tubular NGAL staining) Mori K et al, J Clin Invest. 2005

2-6 h Ι(µg/L) ARF

• NGAL is a biomarker for AKI after cardiac surgery in Ι without ARF NGAL children Urine Mishra J et al, Lancet 2005

• In a cohort of adults who developed AKI after cardiac surgery, urinary NGAL was significantly elevated by 1-3 hrs after the operation Wegener G et al, Anesthesiology 2006

• NGAL levels in biopsies specimens and in urine after kidney transplantation clearly predict Delayed Graft Function onset and requirement of RRT Mishra J et al, Pediatr Nephrol. 2006; Parikh CR et al, Am J Transpl. 2006

Interleukin-18

• Proinflammatory cytokine induced and cleaved in the proximal tubule after AKI. The active

form of IL-18 exits the cell and may enter the urine after being activated in proximal tubules.

• In mice, urinary IL-18 concentration was increased in ischemic AKI compared with sham-surgery controls. (Melnikov VY et al, J Clin Invest 2001)
• Urine IL-18 levels were markedly increased in pts with established AKI but not in subjects with UTI, CKD, nephritic syndrome, or prerenal failure (ROC AUC of 95% for the diagnosis of established AKI). (Parikh CR et al, Am J Kid Dis 2004)

IL-18 seems to be an excellent tool to differentiate ATN from other types of acute renal diseases. IL-18 may predict development of AKI, requirement of RRT and mortality.

• In acute respiratory distress syndrome (ARDS) urine IL-18 levels of >100pg/mg predicted the development of AKI 24 hrs before the serum creatinine (OR 6.5; ROC AUC 0,73). Urine IL-18 predicted also mortality in ARDS. (Parikh CR et al, J Am Soc Nephrol 2005)

AKI

• In 137 critically ill pediatric pts, urine IL-18 rose 48h before SCr in non-septic

• Cysteine protease inhibitor synthesized and released into the blood at a relatively constant rate by all nucleated cells
• Freely filtered by the glomerulus, completely reabsorbed by the proximal tubule, and not secreted
• It is a better predictor of glomerular function than serum creatinine in patients with chronic kidney disease (Grubb AO, Adv Clin Chem 2000)

• At the day of transplant, urine IL-18 levels clearly identified cadaveric kidney recipients who subsequently developed delayed graft function (DGF) and dialysis requirement (Parikh CR et al, Am J Kid Dis 2004; Parikh CR et al, Am J Transplant 2006)
• In children patients after cardiac surgery, urine IL-18 levels increased approximately 6 hours and peaked at over 25-fold at 12 hours. IL-18 was associated with duration of acute kidney injury (Parikh CR, Mishra J et al, Kidney Int. 2006)

C has been shown to predict the requirement for renal replacement therapy in patients with established AKI about 1 day earlier, with an AUC of 0.75 (Herget-Rosental S et al, Clin Chem. 2004).

In the ICU setting, a 50% increase in serum cystatin C predicted AKI 1-2 days before the rise.