© Borgis - Postępy Nauk Medycznych 2/2013, s. 138-143
*Maria Roszkowska-Blaim, Agnieszka Kisiel
Rola biomarkerów we wczesnej diagnostyce ostrego uszkodzenia nerek u noworodków
Role of biomarkers in the early diagnosis of acute kidney injury in neonates
Department of Pediatric Nephrology, Medical University of Warsaw
Head of Department: prof. Maria Roszkowska-Blaim, MD, PhD
Ostre uszkodzenie nerek (AKI – ang. acute kidney injury) jest nagłą, zwykle odwracalną dyfunkcją nerek z obniżeniem filtracji kłębuszkowej (GFR – ang. glomerular filtration rate) oraz uszkodzeniem zdolności nerek do utrzymania homeostazy. Ostre uszkodzenie nerek wiąże się ze wzrostem ryzyka niepomyślnego wyniku leczenia krytycznie chorych noworodków. Precyzyjna liczba incydentów AKI u noworodków nie jest znana, wg danych z literatury, AKI jest wykrywane u 8-24% wśród wszystkich ciężko chorych noworodków. Pomimo znaczącego postępu w leczeniu, stopień śmiertelności jest nadal wysoki i wynosi 10-61%.
Niedoszacowanie AKI w okresie noworodkowym może być spowodowane specyficznym przebiegiem klinicznym, częściej nieoligurycznym niż oligurycznym oraz stosowaniem kreatyniny jako jedynego biomarkera dysfunkcji nerek. Stężenie kreatyniny jest późnym markerem uszkodzenia nerek.
W tym artykule autorzy przedstawiają klasyfikację AKI z uwzględnieniem etiologii i objawów klinicznych, oraz podsumowują znaczenie diagnostyczne wczesnych biomarkerów AKI jak: cystatyna (CysC), neutrofilowa żelatynaza związana z lipokaliną (NGAL), cząsteczka 1 uszkodzenia nerek (KIM-1), interleukina 18 (IL-18), białka wiążące kwasy tłuszczowe typ wątrobowy (L-FABP). Stosowanie nowych biomarkerów w diagnostyce AKI, pozwala wykryć przedkliniczny stan uszkodzenia nerek w okresie noworodkowym.
Niezbędne są dalsze badania na dużej populacji noworodków, co pozwoliłoby wybrać optymalny panel diagnostyczny testów do rozpoznania AKI, pozwalający lepiej wyselekcjonować pacjentów, szybciej zastosować odpowiednie leczenie i poprawić rokowanie.
Acute kidney injury (AKI) is sudden, usually reversible renal dysfunction with reduction of glomerular filtration rate (GFR) and impaired of renal ability to maintain homeostasis. Acute kidney injury is associated with increased risk for poor outcome in critically ill neonates. Precise incidence of AKI in neonates is unknown, literature data suggest that this condition is diagnosed in 8-24% of all critically ill newborns. Despite significant advances in the therapeutics the mortality rate is still high and ranging between 10-61%.
Underestimation of AKI in the neonatal period may be caused by the specific clinical course – more commonly nonoliguric than oliguric and the use of creatinine as the only biochemical marker of kidney disfunction. Serum creatinine is known as a late marker of renal failure.
In this article authors present the classification of AKI in neonates with etiology and clinical presentation and summarize the diagnostic performance of the early predictive biomarkers of AKI: cystatin C (CysC), neutrophil gelatinase-associated lipokalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), liver fatty acid-binding protein (L-FABP). They indicate the use of novel biomarkers in the diagnosis of AKI allows to detect preclinical kidney damage in the neonatal period.
Further studies are required in large neonates populations that would identify optimal panels of diagnostic tests for AKI, allowing better patient selection, more rapid introduction of specific treatment, and improvement in prognosis.
Acute kidney injury (AKI) is sudden, usually reversible renal dysfunction with reduction of glomerular filtration rate (GFR) and impaired excretion of waste products, leading to water-electrolyte and acid-base imbalance. Although precise incidence of AKI in neonates is unknown, literature data suggest that this condition is diagnosed in 8-24% of all critically ill newborns in neonatal intensive care units (1, 2), and preterm infants comprise about one third of the affected patients (2).
AKI in neonates may be underestimated as the disease is often nonoliguric, and postpartum neonatal creatinine level reflects its maternal level (3). In addition, after birth GFR is low in both preterm and full-term infants; GFR increases within first month of life, but velocity of this increase is lower in preterm neonates (4). AKI is associated with increased morbidity and mortality, and prolonged hospitalizations both in children (5, 6) and adults (7). It has been suggested that in neonates, AKI is a risk factor for mortality and long-term chronic kidney disease. Despite advances in treatment, neonatal mortality in AKI is 10-61% (8).
The term “acute renal failure” (ARF) was introduced in 1951 by Homer W. Smith (9), and several dozen varying definitions of ARF have been used in the literature since that time. A classification of ARF in adults, based on creatinine level and diuresis, has been introduced only in 2004 and is known as the RIFLE criteria (Risk of kidney injury, kidney Injury, renal Failure, Loss of kidney function for > 4 weeks, End-stage kidney disease requiring renal replacement therapy for > 3 months) (10, 11). In 2007, a novel 3-stage Acute Kidney Injury Network (AKIN) classification was proposed. According to the AKIN classification, AKI is a rapidly developing (within 48 hours) renal dysfunction defined as an increase in creatinine level by 0.3 mg/dL or 50%, or reduction in urine output to < 0.5 mL/kg/hour for 6 hours (12). With this terminology, AKI is renal dysfunction secondary to structural and functional intrarenal changes, and the term of ARF is reserved for conditions requiring renal replacement therapy.
In 2007, Acan-Arikan published first pediatric RIFLE classification (pRIFLE) for children above 2 years of age, based on the estimated creatinine clearance (using Schwartz formula) and hourly diuresis (5).
In clinical practice, renal dysfunction in neonates is diagnosed based on abnormal results of biochemical tests and reduced urine output. First neonatal AKI classification was proposed by Koralkar in 2011(13). Table 1 shows AKI classification criteria in neonates and children above 2 years of age.
Table 1. Classification for AKI in neonates and children.
|Classification for AKI in neonates*||pRIFLE (> 2 years old)**|
|AKI stages||Serum creatinine (SCr)||AKI stages||eGFR (mL/min/1.73 m2)||Urine output (mL/kg/h)|
|1||↑ SCr ≥ 0.3 mg/dL (26.5 μmoL/L) from previous value = 48 h ↑ SCr ≥ 150-200% from previous value||R||Risk||↓ by 25%||< 0.5/8 h|
|2||↑ SCr ≥ 200-300% from previous value||I||Injury||↓ by 50%|| < 0.5/16 h|
|3||↑ SCr ≥ 2.5 mg/dL (221.0 μmoL/L) ↑ SCr ≥ 300% from previous value or renal replacement therapy||F||Failure||↓ by 75% or < 35|| < 0.3/24 h or anuria/12 h|
AKI – acute kidney injury; eGFR – estimated GFR according to Schwartz formula (14)
Adapted: *(12), **(4)
Etiology of acute kidney injury
No large studies on the etiology of AKI in neonates have been published. In the prenatal period, an important cause of AKI development in utero is exposure to nephrotoxic drugs such as angiotensin-converting enzyme inhibitors (ACEI) (15), angiotensin-receptor blockers (ARB) and non-steroidal anti-inflammatory drugs (NSAIDs) (16) which inhibit prostaglandin secretion, leading to vasodilatation and renal hypoperfusion. Congenital and genetic kidney disease such as renal dysplasia/hypoplasia and cystic kidney disease including autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) may lead to renal failure (8).
In the postnatal period, risk factors for AKI include preterm birth, perinatal asphyxia, respiratory distress syndrome (RDS) requiring ventilation support and surfactant administration and sepsis(17). Table 2 shows the most common causes of acute kidney injury in the neonatal period.
Table 2. Causes of AKI in neonates.
|↓ Intravascular volume ||Dehydratation Gastrointestinal disorders Salt wasting renal/arenal disease Nephrogenic or central diabetes insipidus Third space losses (sepsis, traumatized tissue) |
|↓ Intravascular blood volume||Congestive heart failure Pericarditis Cardiac tamponade|
|Acute tubular necrosis||Hypoxic/ischemic injury|
|Nephrotoxic drugs: aminoglycosides, intravascular contrast, NSAIDs |
|Endogenous toxins: hemoglobinuria, myoglobinemia |
|Interstitial nephritis||Drugs: antibiotics, anticonvulsants|
|Vascular lesions||Cortical necrosis Renal artery/venous thrombosis|
|Infectious causes||Sepsis Pyelonephritis|
|CAKUT||Obstruction in a solitary kidney Bilateral ureteral obstruction|
NSAIDs – non-steroidal anti-inflammatory drugs CAKUT – congenital anomalies of kidney and urinary tract
Clinical presentation of acute kidney injury in neonates
Regardless of patient age, AKI may be traditionally categorized as:
1. prerenal failure due to impaired adaptation to intravascular volume reduction or hypotension,
2. intrarenal failure resulting from the effect of cytotoxic factors that impair nephron structure and function,
3. postrenal failure due to obstructed urine outflow.
The most common type of AKI in neonates is prerenal failure, found in 85% of cases. Intrarenal failure was reported in 11% of cases, and postrenal failure in only 3% of cases (18).
The clinical presentation of AKI includes reduction in urine output to < 0.5-1.0 mL/kg body mass/hour. In the neonatal period, AKI is more commonly nonoliguric than oliguric, and edema is not a characteristic feature but may be caused by water retention due to unrecognized oliguria. In addition, some children present with arterial hypertension (19).
AKI may be diagnosed in the absence of characteristic clinical signs, based on typical abnormal biochemical findings such as increased levels of nitrogen waste products including creatinine, electrolyte disturbances including hyponatremia, hyperkalemia and hypocalcemia, and metabolic acidosis. Hyponatremia may be dilutional in oliguric AKI or depletional in non-oliguric AKI.
Evaluation of acute kidney injury in neonates
Commonly used parameters of renal dysfunction include serum creatinine, urinary sodium, urine osmolality, and fractional sodium excretion (FENa) which allows distinguishing between intrarenal and prerenal failure. In oliguric acute tubular necrosis (ATN) in full-term infants, FENa is always > 2.5-3.0%, and in preterm infants (≤ 32 weeks of gestation) with high plasma sodium level and urinary sodium excretion, diagnostic cut-off FENa for ATN is > 6% (tab. 3). The diagnosis of prerenal AKI is confirmed by an increase in urine output following fluid replacement (8).
Table 3. The differential diagnosis of AKI: prerenal from intrinsic renal based on urine osmolality, urine sodium concentration and fractional Na excretion in newborns.
|Prerenal||Intrinsic renal (ATN)|
|Newborns (full term/preterm)|
|Urine osmolality (mOsm/L)||> 350||< 350|
|Na/urine (mEq/L)||< 20-30||> 30-40|
|FENa (%)||> 2.5||2.0|
FENa – fractional Na excretion; ATN – acute tubular necrosis
AKI is associated not only with reduced GFR but also with functional changes in renal tubular epithelium, interstitial tissue, and intrarenal microcirculation. AKI in neonates is largely asymptomatic, and the diagnosis is based on the determination of serum creatinine, a biomarker of renal function. The main source of creatinine is phosphocreatinine in the muscle tissue. In full-term infants, serum creatinine reflects maternal creatinine levels during the initial 48-72 hours after birth, and then gradually decreases to 0.4 mg/dL by about 2 weeks. In preterm infants, creatinine level initially rises during the first 2-4 days and later normalizes by 2-3 weeks. Unfortunately, creatinine level is a late marker of renal dysfunction, rising only when lesions involve 50% of the renal parenchyma (20). GFR in full-term infants is 20 mL/min/1.73 m2 and doubles within the initial two weeks after birth, while in preterm infants it is low, depends on the gestational age and doubles only by 3 weeks after birth or even later. The rate of GFR changes depends on renal hemodynamic changes that occur regardless of the gestational age and body mass (4). Despite the above limitations, serum creatinine level continues to be widely used as a clinical biomarker of renal function also in neonates.
Intensive search continues for an ideal biomarker to improve the diagnosis of AKI. Such a biomarker should be characterized by:
1. an ability to be determined in easily obtainable biological specimens, preferably using least invasive methods (e.g. urine);
2. high sensitivity for the detection of even mild renal dysfunction;
Powyżej zamieściliśmy fragment artykułu, do którego możesz uzyskać pełny dostęp.
Płatny dostęp do wszystkich zasobów Czytelni Medycznej
1. Agras PI, Tarcan A, Baskin E et al.: Acute renal failure in the neonatal period. Ren Fail 2004; 26: 305-309.
2. Stapleton FB, Jones DP, Green RS: Acute renal failure in neonates: incidence, etiology and outcome. Pediatr Nephrol 1987; 1: 314-320.
3. Askenazi DJ, Koralkar R, Hundley HE et al.: Urine biomarkers predict acute kidney injury in newborns. J Pediatr 2012; 161: 270-275.e1.
4. Hoseini R, Otukesh H, Rahimzadeh N et al.: Glomerular function in neonates. Iran J Kidney Dis 2012; 6: 166-172.
5. Akcan-Arikan A, Zappitelli M, Loftis LL et al.: Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int 2007; 71: 1028-1035.
6. Zappitelli M, Parikh CR, Akcan-Arikan A et al.: Ascertainment and epidemiology of acute kidney injury varies with definition interpretation. Clin J Am Soc Nephrol 2008; 3: 948-954.
7. Ricci Z, Cruz D, Ronco C: The RIFLE criteria and mortality in acute kidney injury: A systematic review. Kidney Int 2008; 73: 538-546.
8. Andreoli SP: Acute renal failure in the newborn. Semin Perinatol 2004; 28: 112-123.
9. Smith HW: Acute renal failure related to traumatic injuries, in The Kidney: Structure and Function in Health and Disease. Oxford University Press, USA 1951.
10. Schrier RW, Wang W, Poole B et al.: Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J Clin Invest 2004; 114: 5-14.
11. Kellum JA, Bellomo R, Ronco C: Definition and classification of acute kidney injury. Nephron Clin Pract 2008; 109: c182-187.
12. Mehta RL, Kellum JA, Shah SV et al.: Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007; 11: R31.
13. Koralkar R, Ambalavanan N, Levitan EB et al.: Acute kidney injury reduces survival in very low birth weight infants. Pediatr Res 2011; 69: 354-358.
14. Schwartz GJ, Haycock GB, Edelmann CM et al.: A Simple Estimate of Glomerular Filtration Rate in Children Derived From Body Length and Plasma Creatinine. Pediatrics 1976; 58: 259-263.
15. Lip GY, Churchill D, Beevers M et al.: Angiotensin-converting-enzyme inhibitors in early pregnancy. Lancet 1997; 350: 1446-1447.
16. Benini D, Fanos V, Cuzzolin L et al.: In utero exposure to nonsteroidal anti-inflammatory drugs: neonatal renal failure. Pediatr Nephrol 2004; 19: 232-234.
17. Cuzzolin L, Fanos V, Pinna B et al.: Postnatal renal function in preterm newborns: a role of diseases, drugs and therapeutic interventions. Pediatr Nephrol 2006; 21: 931-938.
18. Hentschel R, Lödige B, Bulla M: Renal insufficiency in the neonatal period. Clin Nephrol 1996; 46: 54-58.
19. Tóth-Heyn P, Drukker A, Guignard JP: The stressed neonatal kidney: from pathophysiology to clinical management of neonatal vasomotor nephropathy. Pediatr Nephrol 2000; 14: 227-239.
20. Oberbauer R: Biomarkers – a potential route for improved diagnosis and management of ongoing renal damage. Transplant Proc 2008; 40: S44-S47.
21. Devarajan P: Biomarkers for the early detection of acute kidney injury. Curr Opin Pediatr 2011; 23: 194-200.
22. Devarajan P: The Future Of Pediatric Aki Management Biomarkers. Semin Nephrol 2008; 28: 493-498.
23. Armangil D, Yurdakök M, Canpolat FE et al.: Determination of reference values for plasma cystatin C and comparison with creatinine in premature infants. Pediatr Nephrol 2008; 23: 2081-2083.
24. Cataldi L, Mussap M, Bertelli L et al.: Cystatin C in healthy women at term pregnancy and in their infant newborns: relationship between maternal and neonatal serum levels and reference values. Am J Perinatol 2008; 16: 287-295.
25. Herget-Rosenthal S, Poppen D, Hüsing J et al.: Prognostic value of tubular proteinuria and enzymuria in nonoliguric acute tubular necrosis. Clin Chem 2004; 50: 552-558.
26. VandeVoorde RG, Katlman TI, Ma Q et al.: Serum NGAL and cystatin C as predictive biomarkers for acute kidney injury. J Am Soc Nephrol 2006; 17: 404A.
27. Jedrasiak U, Grygalewicz J: The influence of delivery and perinatal risk factors on the concentration of cystatine C in umbilical cord blood. Pol Merkur Lek 2007; 23: 110-115.
28. Li Y, Fu C, Zhou X et al.: Urine interleukin-18 and cystatin-C as biomarkers of acute kidney injury in critically ill neonates. Pediatr Nephrol 2012; 27: 851-860.
29. Askenazi DJ, Koralkar R, Levitan EB et al.: Baseline Values of Candidate Urine Acute Kidney Injury Biomarkers Vary by Gestational Age in Premature Infants. Pediatr Res 2011; 70: 302-306.
30. Novo AC de ACF, Sadeck L dos SR, Okay TS et al.: Longitudinal study of Cystatin C in healthy term newborns. Clinics 2011; 66: 217-220.
31. Sarafidis K, Tsepkentzi E, Agakidou E et al.: Serum and urine acute kidney injury biomarkers in asphyxiated neonates. Pediatr Nephrol 2012; 27: 1575-1582.
32. Nguyen MT, Devarajan P: Biomarkers for the early detection of acute kidney injury. Pediatr Nephrol 2008; 23: 2151-2157.
33. Huynh TK, Bateman DA, Parravicini E et al.: Reference Values of Urinary Neutrophil Gelatinase-Associated Lipocalin in Very Low Birth Weight Infants. Pediatr Res 2009; 66: 528-532.
34. Lavery AP, Meinzen-Derr JK, Anderson E et al.: Urinary NGAL in premature infants. Pediatr Res 2008; 64: 423-428.
35. Han WK, Waikar SS, Johnson A et al.: Urinary biomarkers in the early diagnosis of acute kidney injury. Kidney Int 2008; 73: 863-869.
36. Krawczeski CD, Woo JG, Wang Y et al.: Neutrophil gelatinase-associated lipocalin concentrations predict development of acute kidney injury in neonates and children after cardiopulmonary bypass. J Pediatr 2011; 158: 1009-1015.
37. Parravicini E, Nemerofsky SL, Michelson KA et al.: Urinary neutrophil gelatinase-associated lipocalin is a promising biomarker for late onset culture-positive sepsis in very low birth weight infants. Pediatr Res 2010; 67: 636-640.
38. Ichimura T, Bonventre JV, Bailly V et al.: Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem 1998; 273: 4135-4142.
39. Bonventre JV, Yang L: Kidney injury molecule-1. Curr Opin Crit Care 2010; 16: 556-561.
40. Genc G, Ozkaya O, Avci B et al.: Kidney Injury Molecule-1 as a Promising Biomarker for Acute Kidney Injury in Premature Babies. Am J Perinatol 2012; doi 10.1055/s-0032-1323587.
41. Leslie JA, Meldrum KK: The role of interleukin-18 in renal injury. J Surg Res 2008; 145: 170-175.
42. Parikh CR, Mishra J, Thiessen-Philbrook H et al.: Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int 2006; 70: 199-203.
43. Washburn KK, Zappitelli M, Arikan AA et al.: Urinary interleukin-18 is an acute kidney injury biomarker in critically ill children. Nephrol Dial Transplant 2008; 23: 566-572.
44. Askenazi DJ, Montesanti A, Hunley H et al.: Urine Biomarkers Predict Acute Kidney Injury and Mortality in Very Low Birth Weight Infants. J Pediat 2011; 159: 907-912.e1.
45. Kamijo-Ikemori A, Sugaya T, Kimura K: Urinary fatty acid binding protein in renal disease. Clin Chim Acta 2006; 374: 1-7.
46. Tsukahara H, Sugaya T, Hayakawa K et al.: Quantification of L-type fatty acid binding protein in the urine of preterm neonates. Early Hum Dev 2005; 81: 643-646.
47. Coca SG, Yalavarthy R, Concato J et al.: Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int 2008; 73: 1008-1016.