1. AKI and CRRT: Progress over the last 2 decades! Timothy E Bunchman MD Professor & Director Pediatric Nephrology tbunchman@mcvh-vcu.edu pedscrrt@gmail.com www.pcrrt.com

2. Terminology change * ARF Acute renal failure AKD Acute kidney disease AKI Acute kidney Insufficiency (* No matter the name they are still sick)

3. Creatinine Changes and AKI in Children 390 pediatric cardiac surgery patients Cr rise at 25-50% above baseline within first 24 hours of surgery Increase LOS Increase ventilator days Zappitelli et al, Kid Int 2009 76:885-892

4. Pediatric ARF - Incidence of cases requiring RRT 227 cases in the years 84-91. Yorkshire UK Incidence: 0.8/yr/100.000 total population neonate-infant: 19.7/yr/100.000 age related population 1-4 years: 5.9/yr/100.000 age related population 5-15 years: 1.5/yr/100.000 age related population children: 3.9/yr/100.000 age related population 1/5 of the adult incidence ICU was needed for half the children ARF is often a secondary event (eg sepsis)

5. Etiology of Pediatric ARF (Andreoli SP, Curr Opin in Pediatr, 14:183-188, 2002) HUS Moghal et al, Clin Nephro 49:91-95, 1998 ARF with MOSF Secondary to underlying disease Surgery for congenital heart disease Bone marrow tx Solid organ tx

6. Causes of ARF in Children Current Opinion in Pediatrics, April 1998

7. The etiology of acute renal failure- Nigeria ( Anochie & Eke Peds Neph 2005:20 1610-1614) Etiology Number (%, N=211) Gastroenteritis61 (28.9) Septicaemia32 (15.2) With Tetanus4 (5.3) Acute glomerulonephritis29 (13.7) Plasmodium falciparum malaria29 (13.7) Birth asphyxia27 (12.8) Haemolytic uraemic syndrome7 (3.3) Malignancy6 (2.8) Leukaemia4 Burkitt lymphoma2 HIV related3 (1.4) Congenital malformation10 (4.7) Posterior urethral valves6 Renal agenesis4 Renal vein thrombosis1 (0.5)

8. Pediatric ARF: Disease and Survival Ped Neph 16:1067-1071, 2001

9. Williams et al, Arch Ped Adolesc Med, 2002 Changes with Era's HUS: >25% to ~15% Heme-Onc: 8 to ~18% Sepsis:No change (~1/5) HUS: >25% to ~15% Heme-Onc: 8 to ~18% Sepsis:No change (~1/5)

10. Characteristics, patterns

11. SPECIAL FIBERS AND FILTERS HAVE BEEN DESIGNED FOR SPECIAL CONDITIONS AND PATIENTS Minifilters Ronco C, et al Treatment of acute renal failure in newborns by Continuous Arterio-Venous Hemofiltration. Kidney International, 1984

12. 1980s Following Ronco’s paper little was published except for a descriptive paper by Leone et al describing CAVH in children Early experience with continuous arteriovenous hemofiltration in critically ill pediatric patients. Crit Care Med. 1986 Dec;14(12):1058-63.Crit Care Med. Neonatal work by Zobel Continuous arteriovenous hemofiltration in premature infants. Crit Care Med. 1989 Jun;17(6):534-6. Crit Care Med.

13. 1990s Equipment during this era was “adaptive” Solutions for convection or diffusion was pharmacy made or lactate based Latter part of 1990s industry began to market machines that did not take momentum until turn of the decade

14. 1990s Important work on Access was presented by John Gardner RN describing the MAHURKAR™ Catheter that is now marked by Covidien “how to do it papers” Continuous arterial-venous diahemofiltration and continuous veno-venous diahemofiltration in infants and children. Pediatr Nephrol. 1994 Feb;8(1):96- 102.Pediatr Nephrol. Continuous venovenous hemodiafiltration in infants and children. Am J Kidney Dis. 1995 Jan;25(1):17-21.Am J Kidney Dis. Out come paper by Smoyer et al on Determinants of survival in pediatric continuous hemofiltration. J Am Soc Neph 1995 Nov;6(5):1401-9. Comparison paper on CAVH vs CVVH by our group in Am J Kid Dis 1995 Maxvold and colleagues began comparison of modalities Management of acute renal failure in the pediatric patient: hemofiltration versus hemodialysis. Am J Kidney Dis. 1997 Nov;30(5 Suppl 4):S84-8.Am J Kidney Dis.

15. 1990s Evaluation of PICU needs and RRT beyond AKI began Parekh RS et al Dialysis support in the pediatric intensive care unit. Adv Renal Replac Therapy 1996 Oct;3(4):326-36. Quigley and associates on use of HD and hemofiltration in TLS Hyperphosphatemia in tumor lysis syndrome: the role of hemodialysis and continuous veno-venous hemofiltration. Peds Nephrol 1994, 8: 351-3

16. 2000s This era exploded with advancements in Equipment FDA approval of bicarbonate based Solutions Nutrition in AKI/CRRT Avoidance of complications Anticoagulation protocols

17. 2000s Gambro and B Braun (and soon to follow Baxter) came out with machines with commonality of warmer, accurate fluid control as well as blood flow and solutions controllers

18. 2000s FDA approval of bicarbonate based Solutions by Dialysis Solution Inc and Walter O’Rourke Pediatric hemofiltration: Normocarb dialysate solution with citrate anticoagulation. Pediatr Nephrol 2002 17:150-4 Maxvold et al described Nutrition needs and losses in AKI/CRRT Amino acid loss and nitrogen balance in critically ill children with acute renal failure: a prospective comparison between classic hemofiltration and hemofiltration with dialysis. Crit Care Med 2000 28:1161-5

19. 2000s Additional data on outcome Pediatric acute renal failure: outcome by modality and disease. Pediatr Nephrol 2001, 16:1067-71 Maxvold et al Renal failure and renal replacement therapy. Crit Care Clin 2003 19:563-75 Barletta et al Acute renal failure in children and infants. Curr Opin Crit Care 2004: 10: 499-504

20. 2000s Anticoagulation Protocols Pediatric acute renal failure: outcome by modality and disease. Pediatr Nephrol 2001, 16:1067-71 Pediatric convective hemofiltration: Normocarb replacement fluid and citrate anticoagulation. Am J Kid Dis 2003 42: 1248-52 Brophy et al Multi-centre evaluation of anticoagulation in patients receiving continuous renal replacement therapy (CRRT). NDT 2005 20:1416- 21

21. Indications Ronco et al CRRT at initiation results in improved survival Lancet. 2000 Jul 1;356(9223):26-30. Fluid overload Lane et al Bone Marrow Transplant. 1994 May;13(5):613-7. Goldstein et al Pediatrics. 2001 Jun;107(6):1309-12. Paden et al Crit Care Med. 2004 Aug;32(8):1771-6. Symons et al Pediatr Nephrol. 2004 Dec;19(12):1394-9.

22. Infants AKI and IBEM Symons et al Am J Kidney Dis. 2003 May;41(5):984-9. Askenazi DJ et al J Pediatr. 2013 Mar;162(3):587-592. Picca et al Leader in the field of in born error of metabolism and RRT Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators. Pediatr Nephrol. 2001 Nov;16(11):862-7. Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators.

23. Complications Brophy et al AN-69 membrane reactions are pH-dependent and preventable. Am J Kid Dis 2001 38:173-8 Barletta et al Medication errors and patient complications with continuous renal replacement therapy. Pediatr Nephrol 2006 21:842-5 Johnson P et al Thermic control and heat loss in CRRT presented at the CRRT meeting in San Diego abst only

24. Beginning of the meetings and cooperative studies CRRT San Diego began in 1996 PCRRT meetings began in 2000 PCRRT meetings arose from a discussion with Christian Schlaeper (Fresenius) ppCRRT registry began is 2006

25. ppCRRT Registry An Idea of Stu Goldstein that brought together 13 + programs to pool data based upon local standard of care The ppCRRT registry was responsible for 15 manuscripts from multiple authors

26. ppCRRT representative papers Flores FX et al Continuous renal replacement therapy (CRRT) after stem cell transplantation. A report from the prospective pediatric CRRT Registry Group.Pediatr Nephrol. 2008 Apr;23(4):625-30.Continuous renal replacement therapy (CRRT) after stem cell transplantation. A report from the prospective pediatric CRRT Registry Group. Hackbarth R et al The effect of vascular access location and size on circuit survival in pediatric continuous renal replacement therapy: a report from the PPCRRT registry. Int J Artif Organs. 2007 Dec;30(12):1116-21.The effect of vascular access location and size on circuit survival in pediatric continuous renal replacement therapy: a report from the PPCRRT registry.

27. Tandem therapies Meyer RJ et al Hemodialysis followed by continuous hemofiltration for treatment of lithium intoxication in children. Am J Kidney Dis. 2001 May;37(5):1044-7.Hemodialysis followed by continuous hemofiltration for treatment of lithium intoxication in children. Phenylacetate and benzoate clearance in a hyperammonemic infant on sequential hemodialysis and hemofiltration. Pediatr Nephrol. 2007 Jul;22(7):1062-5. Epub 2007 Feb 3. Phenylacetate and benzoate clearance in a hyperammonemic infant on sequential hemodialysis and hemofiltration.

28. Use of RRT in Intoxications EXTRIP.org Ferris et al Management of toxic ingestions with the use of renal replacement therapy. Pediatr Nephrol. 2011 Apr;26(4):535-41Management of toxic ingestions with the use of renal replacement therapy.

29. RRT and ECMO Meyer RJ Survival and renal function in pediatric patients following extracorporeal life support with hemofiltration. Pediatr Crit Care Med. 2001 Jul;2(3):238-242.Survival and renal function in pediatric patients following extracorporeal life support with hemofiltration. Hoover NG Enhanced fluid management with continuous venovenous hemofiltration in pediatric respiratory failure patients receiving extracorporeal membrane oxygenation support. Intensive Care Med. 2008 Dec;34(12):2241-7Enhanced fluid management with continuous venovenous hemofiltration in pediatric respiratory failure patients receiving extracorporeal membrane oxygenation support.

30. RRT and ECMO Askenazi DJ Acute kidney injury and renal replacement therapy independently predict mortality in neonatal and pediatric noncardiac patients on extracorporeal membrane oxygenation. Pediatr Crit Care Med. 2011 Jan;12(1):e1-6.Acute kidney injury and renal replacement therapy independently predict mortality in neonatal and pediatric noncardiac patients on extracorporeal membrane oxygenation.

31. Liver Disease and CRRT Deep A et al Factors affecting circuit life during continuous renal replacement therapy in children with liver failure. Ther Apher Dial. 2015 Feb;19(1):16-22Ther Apher Dial. Deep A and colleagues Prostacyclin (epoprostenol) As An Anticoagulant In Continuous Renal Replacement Therapy (CRRT) In Paediatric Acute Liver Failure (PALF) ( Abstract) Arch Dis Child 2014;99:Suppl 2 A100-A101

32. Definitions RIFLE pRIFLE AKIN KDIGO Urine out put Changes in Creatinine Cystatin C

33. Urine NGAL as an Early AKI Biomarker after Cardiopulmonary Bypass AKI = 50% or greater increase in serum creatinine from baseline Mishra et al, Lancet 2005, 365:1231-1238

34. Advancement in Equipment CARPEDIUM (Ronco) Nidus (Coulthard) Aquadex (Askenazi) Japanese small circuit (Ishikawa)

35. Where is research needed Over incidence of AKI AWARE study recently published Timing of intervention Optimal nutritional dosing Optimal drug dosing

36. I have worked with Giants (by no means is this list inclusive) Maxvold Brophy Barletta McBryde Goldstein Askenazi Zappitelli Picca Parekh McCulloch Deep Hackbarth Flores Quigley Ronco Symons Flores Ferris Fortenberry Raina