Infant Acute Kidney Injury

1. Infant Acute Kidney Injury Maricor Grio, MD, MS Orlando Health Arnold Palmer Hospital for Children Orlando, Florida Maricor.Grio@orlandohealth.com

2. Infant AKI • How common is this problem? • What are the causes? • Who are the patients at risk? • What are the prevention and treatment options? • What are the long term consequences?

3. Definition of AKI • Reduction of GFR to a level insufficient to adequately filter and excrete solute and water and maintain fluid and electrolyte balance • Urine volume below 0.5-1ml/kg/hr after 1st day • Urine volume is a poor indicator of renal function • Increased serum creatinine > 1.5mg/dl • Serum creatinine is a poor indicator of renal function • Daily rise in serum creatinine of 0.3mg/dL to 0.5 mg/dL?

4. Creatinine Clearance According to Gestational Age Chevalier.J Urol.1996:156

5. Serum Creatinine During First Three Months in LBW Infants < 2000g Stonestreet. Pediatr.1978:61:788-789

6. Incidence and Epidemiology of AKI • Precise incidence and prevalence is unknown • Incidence of AKI in NICU patients is 6-24% • 60% non-oliguric / 25% oliguric / 15% anuric • Higher incidence in patients undergoing cardiac surgery • More common in neonates with severe asphyxia • Some infants may have genetic risk factors for development of AKI Andreoli. Seminars in Perinat.2004:28 (2):112-123

7. Pediatric AKI Epidemiology at a Tertiary Care Center 1999-2001 (n=254 pts) Hui-Stickle et al. AJKD.2005: 45:96

8. AKI in Neonates 1999-2001 n=62 pts • Ischemic ATN most common in 16 pts (26%) • Estimated GFR 11.5 + 89.8 ml/1.73m2 • 56% survived • Length of ICU stay 97 days • 58% required renal replacement therapy Hui-Stickle et al. AJKD.2000545:96

9. Infant AKI • How common is this problem? • What are the causes? • Who are the patients at risk? • What are the prevention and treatment options? • What are the long term consequences?

10. Etiology of AKI Pre-renal AKI Intrinsic AKI Obstructive AKI Prenatal AKI

11. Etiology of Prenatal AKI • Obstructive uropathy • Renal hypoplasia/dysplasia • Renal cystic disease • Agenesis • Nephrotoxic agents • Intrauterine infection • Intrauterine medications- NSAIDs, ACE-i • Complications during pregnancy and delivery

12. Hypovolemia Dehydration Gastrointestinal losses Hemorrhage Salt wasting (renal or adrenal) Central or nephrogenic diabetes insipidus Third space losses (sepsis, traumatized tissue) Cardiac Failure Congenital heart disease Congestive heart failure Pericarditis Cardiac tamponade Etiology of Pre-renal AKI

13. Hypotension Sepsis DIC Bleeding hypothermia Hypoxemia Neonatal asphyxia Severe hyaline membrane disease Pneumonia Cardiac surgery Etiology of Pre-renal AKI

14. Acute Tubular Necrosis Ischemic / hypoxic insults Drug induced Aminoglycosides NSAIDS Antifungal agents Antiviral agents Chemotherapy Intravascular contrast Toxin mediated Uric acid nephropathy Hemoglobinuria Myoglobinuria Interstitial Nephritis Infectious Drug induced Idiopathic Vascular Lesions Cortical necrosis Renal artery thrombosis Renal vein thrombosis Infectious Causes Sepsis Pyelonephritis Etiology of Acquired Intrinsic AKI

15. Etiology of Congenital Intrinsic AKI • Bilateral renal agenesis • Dysplasia/ Hypoplasia • Cystic renal diseases • Congenital nephrotic syndrome • Congenital nephritis

16. Etiology of Obstructive AKI • Congenital obstructive uropathy • Obstruction in a solitary kidney • Bilateral UPJO • Bilateral UVJO • Large obstructive ureterocele • Posterior urethral valves • Urethral stenosis/atresia • Neurogenic bladder • Acquired obstruction • Foley catheter obstruction • Fungus balls • Urethral trauma • External compression

17. Posterior urethral valves

18. Hydronephrosis

19. Cystic Renal Disease

20. Infant AKI • How common is this problem? • What are the causes? • Who are the patients at risk? • What can we do to prevent this problem? • What are the prevention and treatment options? • What are the long term consequences?

21. Prematurity LBW infants IDM CHD Perinatal asphyxia Sepsis RDS Ventilators Vasopressors Volume depletion Hemorrhage Aminoglycosides NSAIDS Antifungal Chemotherapy Hemolysis Postoperative (cardiac) Contrast Agents Patients at Risk

22. AKI in Asphyxiated Term Neonates Points 0 1 2 3 Karlowics. Ped. Nephrol.1995 % of pts

23. TNF-, IL-1B, IL-6 & IL-10 haplotype variants in VLBW infants with AKI & non-AKI *p<0.05 * % Vasarheli et al. Pediatr Nephrol .2002:17:713

24. Variance of ACE and AT1 receptor gene in VLBW infants with AKI and non-AKI % Vasarheli et al. Pediatr Nephrol .200116:1063

25. Diagnostic Evaluation in AKI • Prenatal history • Family history • Medications • Oligohydramnios • Complications during pregnancy • Prenatal ultrasounds • Delivery • Fetal distress • Bleeding • Infections • Medications

26. Clinical Evaluation of AKI • Chart review • Intake and output • Infections • Respiratory distress • Medications • Contrast studies • Surgical procedures • Physical examination • General appearance (Potter’s sequence) • Hydration status • Cardiac examination • Pulmonary examination • Abdominal masses

27. Diagnostic Evaluation in AKI • Laboratory studies • Urinalysis and culture • Urine electrolytes / creatinine / osmolality • Urine protein / creatinine • Electrolytes BUN and creatinine / osmolality • Calcium / phosphorus and uric acid • Imaging studies • Renal ultrasound with doppler • VCUG • CT • Renal scan (DTPA or MAG3) • Echocardiogram • CXR

28. Diagnostic studies in AKI

29. Infant AKI • How common is this problem? • What are the causes? • Who are the patients at risk? • What are the prevention and treatment options? • What are the long term consequences?

30. Treatment of AKI Conservative Medical Therapy Renal Replacement Therapy Renal Transplantation

31. Conservative treatment in AKI • Avoiding other nephrotoxic insults • Antibiotics • Antifungal • NSAIDS • Contrast agents • Surgical procedures • Fluid allowance • Insensible losses • Ongoing losses

32. Insensible Water Loss During the First Week of Life Clolherty. Manual of Neonatal Care.1998

33. Prematurity: 100-300% Radiant Warmer: 50-100% Phototherapy: 25-50% Hyperventilation: 20-30% In. activity: 5-25% Hyperthermia: 120C Incubator: 25-50% Humidified air: 15-30% Sedation: 5-25% Dec. activity: 5-25% Hypothermia: 5-15% Factors Affecting Insensible Water Losses

34. Protein Requirements in Newborns with AKI Protein g/kg/d Yiu VW et al. J Renal Nutr .1996.6:203

35. Energy, Calcium and Phosphorus Requirements in Newborns with AKI Yiu VW et al. J Renal Nutr.1996 6:203

36. Conservative Management of AKI • Adjustments of medications according to renal function • Prevention and management of complications • Fluid overload with HTN and RDS • Electrolyte imbalance • Sodium • Potassium • Uric acid • Metabolic acidosis • Anemia • Bone and mineral metabolism disorders • Hypocalcemia • Hyperphosphatemia

37. Treatment of AKI • Dopamine • Diuretics • Phosphorus binders • Non-dialytic treatment for hyperkalemia • NaHC03: 1-2meq/kg IV over 10-30 min • Glucose / Insulin: (0.5g/kg) /( 0.1U/kg) IV over 30 min • Calcium gluconate (10%): 0.5-1cc/kg IV over 5-15 min • B-Agonist (albuterol): 5-10mg nebulizer in adults 2.5mg in children? • Kayexalate (0.5-1g/kg) PO or PR Q6h

38. Future Therapy to Decrease Injury and Promote Recovery? • IGF-1 • ANP • Epidermal growth factor • Hepatocyte growth factor • Melatonin stimulating factor • Thyroxine • C5a receptor antagonist • Selective inhibitors of inducible nitric oxide synthase • Inhibition of monocyte chemoattractant protein-1

39. Theophylline Prophylaxis in Perinatal Asphyxia • Randomized, placebo controlled study • Single theophylline dose vs. placebo (n=70) • Theophylline group (n=40) ; placebo group( n=30) • Higher GFR and lower beta 2 microglobulin excretion in theophylline group • Single dose theophylline (8mg/kg) in the 1st hour of birth may prevent AKI in asphyxiated term infants Bhat et al..J Pediatr.2006:149:180-184

40. Indications for Renal Replacement Therapy (RRT) • Oliguria with fluid overload • Respiratory distress • Hypertension • CHF • Electrolyte imbalance • Hyperkalemia • Hyponatremia • Hyperphosphatemia • Hypocalcemia • Hyperuricemia • Uremic symptoms • Nutritional needs • Others (blood products, medications, other fluids)

41. Options for RRT • Peritoneal dialysis • Manual PD • Cycler PD • Hemodialysis • Continuous renal replacement therapy • CAVH • CAVHD • CVVH • CVVHD

42. Renal Replacement Modality Beisha et al. Pediatr. Nephrol.1995

43. Access less of a problem No special equipment needed Can be done by NICU nurses Can be done in pts of all size Less need for blood products No need for anticoagulation Gradual change in volume and electrolyte composition Relatively few if any contraindications Recent abdominal surgery Ostomies V-P shunt? Peritonitis? Peritoneal scarring Abnormal anatomy Modality of choice for infants with ESRD Peritoneal Dialysis

44. Hemodialysis in Infants Less Than 5Kg • 216 acute hemodialysis treatments 1980-1991 • 33 pts (32-43wks) with wt of 2.2-4kg / total of 216 treatments • Age 2-120 days (median 10 days) • Indications for hemodialysis • Hyperammonemia (8pts) • Intrinsic or primary renal disease (7pts) • Acute kidney injury (18pts) • Hemodialysis Access • 7 Fr double lumen catheter (49%) • ECMO circuit (24%) • Umbilical vessels (27%) Jabs et al. KI.Vol45.1994.903-906

45. Hemodialysis in Infants Less Than 5Kg • 9 Rx discontinued prematurely • Hypotension • Technical problems • Mortality not influenced • Weight • # of HD treatments % survival Jabs et al. KI.Vol45.1994.903-906

46. Who are the non-candidates for RRT? • Severe neurological injury • Inoperable life threatening congenital heart disease • Severe lung disease • Severe congenital anomalies • Extreme prematurity? • Anticipated mortality? • Parents wishes need to be considered • The decision needs to be individualized • Close communication with parents is important

47. Factors Influential in Deciding to initiate ESRD in Infants 217 Pediatric Nephrologist Around the World Family socioeconomic status 1.8 + 1.7 1.7 + 1.7 Hospital / Government budget 0.5 +1.1 0.5 + 0.9 Family’s right to decide 3.7 + 1.3 4.0 + 1.2 Doctor’s right to decide 2.9 + 1.3 3.0 + 1.3 Coexistent serious medical abnormalities 4.8 + 0.6 4.8 + 0.5 Anticipated morbidity for child 4.1 + 1.2 4.3 + 1.0 Presence of oliguria 1.8 + 1.8 1.9 + 1.9 No influence = 0 Strong influence = 5 Responses 1-12 mo (x + SD) Geary et al. J Pediatr.1998:133:154

48. If parents reject RRT for otherwise normal infants with ESRD, is this USUALLY or EVER ethically acceptable to you ? Usually acceptable Ever acceptable < 1mo 1-12mo < 1mo 1-12mo Canada 6/11 2/16 11/12 11/16 France 4/7 3/10 5/7 8/11 Germany 13/19 11/25 19/19 18/25 Holland 1/3 0/3 3/3 3/3 Italy 0/5 0/7 2/6 0/7 Japan 3/11 2/13 3/11 3/13 UK 19/26 5/26 25/26 20/25 USA 38/88 24/93 71/89 59/98 Unidentified 3/4 0/6 3/3 4/6 Total 87/174 49/199 142/176 126/204 Geary et al. J Pediatr.1998. 133:154

49. Infant AKI • How common is this problem? • What are the causes? • Who are the patients at risk? • What are the prevention and treatment options? • What are the long term consequences?

50. Outcome and Prognosis • Highly dependent on the etiology of AKI • Factors associated with poor prognosis • Multiorgan system failure • Hypotension / hemodynamic instability • Need for pressors • RDS with need for mechanical ventilation • Oligoanuria and need for dialysis • Overall mortality 10-61% • Nephron loss can lead to long-term complications • Proteinuria • Hypertension • Chronic renal insufficiency