1. Pediatric Bone Marrow Transplant Recipients with Acute Renal Failure Stuart L. Goldstein, MD Assistant Professor of Pediatrics Baylor College of Medicine

2. Introduction  Acute Renal Failure (ARF) is a common complication in patients with BMT  ARF in adult BMT pts: 30-80%  ARF in pediatric 66 BMT pts: 21% * 11% with CRF 1yr post BMT * Kist-van Holthe JE et al, Ped Neph (2002), 17(12): 1032-1037

3. Causes of ARF in BMT Patients  ARF is usually multi-factorial Early ARF (0 to 60 days) – Acute tubular necrosis (ATN) – Veno-occlusive disease (VOD) – Septic shock – Nephrotoxic medications Late onset ARF (3 to 12 months) – Cyclosporine toxicity – Radiotherapy-induced nephropathy

4. Pediatric Studies of BMT Recipients with ARF  Lane et al (1994) (n=30) Sepsis most common cause of ARF and death Factors associated with persistent renal failure – > 10% Fluid Overload (%FO) – > 3 pressors – Hyperbilirubinemia  Todd et al (1994) (n=54) Increased mortality – Multiple organ system failure – Primary pulmonary parenchymal disease

5. Pediatric Studies of BMT Recipients with ARF  Bunchman et al (2001) (n=26) BMT pts with ARF requiring RRT had 42% survival rate  Greater survival for those required only HD (78%) compared to PD (33%) or HF (21%) Outcome of children requiring RRT directly related to the underlying diagnosis as well as their requirement for pressors

6. ARF and Fluid Overload  BMT pts with ARF are at risk of FO Pre-transplant conditioning can cause small vessel injury and extravascular fluid extravasation Need for large volume requirement – blood products – total parenteral nutrition – multiple antibiotics

7. Fluid Overload  Goldstein et al (2001) reported in a review of critically ill children who received CRRT Increasing degrees of FO prior to initiation of CRRT was associated with greater mortality Postulated early initiation of CRRT prior to development of FO might lead to improved outcome

8. Current Practice at TCH BMT Unit  TCH Renal/BMT ARF protocol developed (Jan’99) for the prevention and treatment of FO in BMT pts with ARF  Pts at 5% FO are started on furosemide and low-dose dopamine drips  RRT/CRRT initiated at > 10% FO and – 50% rise in serum creatinine or – 50% decrease in daily urine output

9. % FO * = [ Fluid In (L) - Fluid Out (L) Pre BMT Weight (kg) ] * 100% Fluid Overload Fluid In = Total Input in Liters Since Admission for BMT Fluid Out = Total Output in Liters Since Admission for BMT

10. Objective  To determine if prevention of severe fluid overload improves outcome in pediatric patients with BMT and ARF

11. Methods  Retrospective chart review of all pts with BMT and ARF from Jan 1999 – Jan 2002  ARF: doubling of baseline serum creatinine  Outcome measure: Survival at ARF resolution/RRT termination  Data analysis: Non-parametric tests (chi-square or Fisher’s exact test) p -value <0.05 significant Michael M: Ped Neph 2004 19:91-5

12. Results  Patient Characteristics 272 pts received allogeneic BMT All received chemo/radio therapy for pre- transplant conditioning and GVHD prophylaxis Underlying diseases: AML, ALL, aplastic anemia, CML, NHL, HL, VAHS, leukodystrophy and myelodysplastic syndrome Michael M: Ped Neph 2004 19:91-5

13. Results  33 ARF episodes in 29 patients (11%)  Excluded ARF episodes: 4 second ARF episodes (100% mortality) 3 patients with non-oliguric ARF  26 initial oliguric ARF episodes analyzed Mean patient age 13 + 5 years (2-23.5) Mean days to ARF after BMT: 28 + 29 days (2-90); 4 pts had ARF at 60-90 days Michael M: Ped Neph 2004 19:91-5

14. Results  ARF Characteristics Etiology – Acute tubular necrosis (n=1) – Nephrotoxic meds (n=16) – ATN/Septic shock+Nephrotoxicity (n=9) Renal function – Mean baseline Cr: 0.62 + 0.36 mg/dl – Mean peak Cr: 3.51 + 1.62 mg/dl – Mean lowest GFR est : 30.5 + 13.5 ml/min/1.73m 2 Michael M: Ped Neph 2004 19:91-5

15. Results  ICU Characteristics 23/26 with ICU admission Mean Pediatric risk mortality (PRISM) score 10.5 + 5 (5-20) Mean maximum % FO : 9 + 5% (3 -18%) 14/26 with renal replacement therapy (RRT) – 11/14 received CRRT – 3/14 received intermittent HD Michael M: Ped Neph 2004 19:91-5

16. Results  Patient Outcome 11/26 (46%) pts survived an initial ARF episode All 11 survivors were <10 %FO at ARF resolution/RRT termination 4/14 RRT (28%) treated patients survived – 2/3 HD (67%) – 2/11 CRRT (18%) Michael M: Ped Neph 2004 19:91-5

17. 10 RRT2 non-RRT 3 <10% FO12 >10% FO 4 RRT (2 HD & 2 CVVHD)All 4 re-attained <10% FO 7 remained >10%FO 3 re-attained <10%FO 11 (46%) survived 15 (54%) died 26 ARF pts Patient Outcome: 4 >10% FO (max 12%) 7 remained <10% FO

18. Summary of Survival and Non-survival Data Clinical Variables SurvivalNon-Survival p value Always <10% FO7/11 (64%)3/15 (20%)< 0.03 Ventilation6/11 (55%)14/15 (93%)< 0.05 PRISM score >10 2/8 (25%)11/15 (73%)< 0.05 Pressor >12/11 (18%)8/15 (53%)0.0687 Sepsis7/11 (63%)13/15 (86%)0.1685 RRT treated4/11 (36%)10/15 (66%)0.1257

19. TCH BMT Study  All patients who remained >10% FO despite starting RRT died  All survivors maintained or re-attained <10% FO  Mechanical ventilation and PRISM score >10 at ICU admission correlated with patient death  Despite prospective intention to prevent severe FO, survival was <50% in pediatric BMT patients with ARF Michael M: Ped Neph 2004 19:91-5

20. TCH BMT Study: Conclusion  Maintenance or re-attainment of < 10% fluid overload is necessary but not sufficient for survival of BMT pts with ARF  Aggressive management with diuretics and early initiation of RRT to prevent worsening %FO may improve survival of these patients Michael M: Ped Neph 2004 19:91-5

21. Stanford ICU/BMT/CRRT study  10 patients with ARDS 6 BMT, 3 chemotherapy, 1 hemophagocytosis Serum creatinine 0.2 to 1.2 mg/dL in six children Serum creatinine 1.7 to 2.4 mg/dL in four children  CVVHDF initiated coincident with intubation regardless of fluid status or renal function (one exception) 3000 ml/1.73m 2 /hour 13 +/- 9 days DiCarlo JV et al: J Pediatr Hematol Oncol. 2003 25:801-5

22. Stanford ICU/BMT/CRRT study  9/10 patients successfully extubated  8/10 patients survived 4/6 BMT patients survived 4/4 Chemotherapy patients survived  Conclusion: early initiation of hemofiltration for intubated BMT patients may prevent progressive inflammatory lung injury and/or worsening fluid overload DiCarlo JV et al: J Pediatr Hematol Oncol. 2003 25:801-5

23. ppCRRT BMT Patient Data  22 patients January 2001 – December 2003) Median age 9.45 years (range 2.2 - 23.5 years)  CRRT modalities CVVHD (45%) CVVH (41%) CVVHDF (14%)  Diagnoses leading to CRRT Sepsis (18%) Hepatorenal syndrome (14%) No single Dx (54%)  8/22 (36%) patients survived Flores FX et al for the ppCRRT: 9 th CRRT meeting, San Diego, March 2004

24. ppCRRT BMT Data: Clinical Variables Flores FX et al for the ppCRRT: 9 th CRRT meeting, San Diego, March 2004 *p<0.05, **p<0.01

25. CRRT for Pediatric BMT Summary  Most studies still demonstrate poor survival for this population  Early initiation of CRRT and aggressive diuresis to prevent fluid overload seems to be necessary, but not sufficient for pediatric BMT patients with ARF  Early hemofiltration may the inflammatory response for intubated pediatric BMT patients