Pediatric Bone Marrow Transplant Recipients with Acute Kidney Injury Stuart L. Goldstein, MD Associate Professor of Pediatrics Baylor College of Medicine

Pediatric AKI Risk Factors: Stem Cell Transplant Recipients AKI in stem cell transplantation results from:  Nephrotoxic medications  Radiation nephritis (post-SCT HUS)  Veno-occlusive disease (hepatorenal syndrome)  Sepsis Early pediatric study 1 ( ) revealed 50% AKI rate after SCT Recent studies describe AKI epidemiology in pediatric SCT with lower TBI doses 1. Van Why SK et al: Bone Marrow Transplant 7:383, 1991

AKI in SCT Patients: Timing Early AKI (0 to 60 days)  Acute tubular necrosis (ATN)  Veno-occlusive disease (VOD)  Septic shock  Nephrotoxic medications Late onset AKI (3 to 12 months)  Cyclosporine/tacrolimus toxicity  Radiation nephritis  Sepsis

Prospective single center study of 66 patients who received SCT over a 2 year period AKI defined as SCr doubling in first 3 months Cyclosporine given to 60 patients  IV (2 mg/kg/dose) for 30 days  Orally (6 mg/kg/day) 3-6 months  200 pg/ml target level

21% AKI rate Conditioning regimen nor malignancy associated with AKI VOD, CYA trough >200, foscarnet use associated with AKI development AKI associated with CKD development (OR 8.0) at one year

Pediatric SCT Recipients with AKI Lane et al (1994) (n=30)  Sepsis most common cause of AKI 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

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

Retrospective evaluation of 226 children who received RRT for AKI from patients with SCT Pressor use surrogate marker for patient severity of illness Survival defined at PICU discharge

AKI and Fluid Overload SCT pts with AKI are at risk for serious sequlae of FO  Pre-transplant conditioning causes small vessel injury and extravascular fluid extravasation  Need for large volume requirement blood products total parenteral nutrition multiple antibiotics

% FO at CVVH initiation = [ Fluid In - Fluid Out ICU Admit Weight ] * 100% Fluid In = Total Input from ICU admit to CRRT initiation Fluid Out = Total Output from ICU admit to CRRT initiation

Lesser % FO at CVVH (D) initiation was associated with improved outcome (p=0.03) Lesser % FO at CVVH (D) initiation was also associated with improved outcome when sample was adjusted for severity of illness (p=0.03; multiple regression analysis)

Seven center study from the ppCRRT Registry 116 patients with MODS PRISM 2 score used to assess patient severity of illness Survival defined at PICU discharge

Retrospective single center review of SCT patient AKI fluid/RRT management algorithm  Furosemide infusion at 5% fluid overload  RRT at 10% fluid overload AKI defined as doubling of SCr or >10% FO from hospital admission 29 patients with 32 AKI episodes in 272 SCTs  4 patients with 2 nd AKI (all died)  1 patient with pre-renal azotemia  3 patients with non-oliguric AKI  First AKI rate of 11%

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

AKI Characteristics  Etiology Acute tubular necrosis (n=1) Nephrotoxic meds (n=16) ATN/Septic shock+Nephrotoxicity (n=9)  Kidney function Mean baseline Cr: mg/dl Mean peak Cr: mg/dl Mean lowest GFR est : ml/min/1.73m 2

ICU Characteristics  23/26 with ICU admission  Mean Pediatric risk mortality (PRISM) score (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

Clinical Variables Survival Non-Survival p 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%)0.07 Sepsis7/11 (63%)13/15 (86%)0.17 RRT treated4/11 (36%)10/15 (66%)0.13

All patients who remained >10% FO despite starting RRT died All survivors maintained/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

51/370 patients in the ppCRRT with SCT 28/51 male AKI/CRRT causes  Multi-factorial (33%)  Respiratory (18%)  Sepsis (16%)  VOD (16%)  MODS (12%)  Nephrotoxins (8%)

Non-survivors succumbing to primary pulmonary process and not excessive FO?

Patients requiring ventilatory support has lower survival (13/37 vs. 10/14, p<0.05) Patients with MODS had nearly two-fold increase in mortality Patients who received some convective CRRT had improved survival (17/29 versus 6/22, p<0.05)

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 :801-5

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 :801-5

CRRT for Pediatric SCT 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 SCT patients with AKI Early CRRT may blunt the inflammatory response and prevent need for intubation or increase likelihood of extubation