Cell based Therapies in Kidney Disease · 2014-01-08 · Cell‐based Therapies in Kidney Disease...
Transcript of Cell based Therapies in Kidney Disease · 2014-01-08 · Cell‐based Therapies in Kidney Disease...
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Cell based Therapies in Kidney DiseaseCell‐based Therapies in Kidney Disease
Mark Rosenberg M.D.Mark Rosenberg M.D.Vice Dean and Professor of Medicinei i f i di l S h lUniversity of Minnesota Medical School
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Case PresentationCase Presentation
ld di b i d i d h• 58 year old diabetic man admitted to the ICU with an acute anterior MI
• Baseline creatinine 3.1 (diabetic nephropathy)• Persistent chest pain⇒ angiography andPersistent chest pain ⇒ angiography and emergent CABG
• Post op hypotension (80/45) responds to• Post‐op hypotension (80/45) responds to pressors
• Progressive increase in serum creatinine over the next few days 3.1 to 3.4 to 3.8 to 4.2
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Evaluation and TreatmentEvaluation and Treatment
• Optimization of hemodynamics• Initiation of dialysis on POD 4 because of K=6,Initiation of dialysis on POD 4 because of K 6, oliguria, and 30 pound weight gain with serum creatinine 4 2creatinine 4.2
• Every other day dialysis to maintain electrolyte and volume status
• Discharged POD 22 off dialysis• Discharged POD 22 off dialysis• Chronic dialysis initiated 6 months later
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Looking under the microscopeLooking under the microscope
ATN
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A t Kid I jAcute Kidney InjuryI id 30 1 illi l ti• Incidence 30 cases per 1 million population
• 5% of hospitalized patients• 30% of ICU patients• High short‐term mortalityHigh short term mortality
• 40 to 70% mortality rate• Mortality dependent on underlying diseaseMortality dependent on underlying disease• Prognosis not significantly improved despite dialysis
– Mortality rate:Mortality rate:• WWII 91%• Korea 68%• Vietnam 67%
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Probability of ESRD & death after li h it l di h b AKI t tlive hospital discharge, by AKI status
General Medicare patients age 66 & older on 12/31/2006, continuously enrolled in Medicare inpatient/outpatient &inpatient/outpatient & physician/supplier coverage, & with no HMO coverage, surviving in 2006. AKI defined in 2006. Excludes patients whose ESRD date is onwhose ESRD date is on or before the AKI discharge date. Patients followed to a maximum of one year after AKI discharge date for those with AKI or Jan.1, 2007 for those without AKI. A one-year entry period before follow-up is used to define CKD status and comorbid conditionscomorbid conditions.
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Acute Tubular NecrosisAcute Tubular Necrosis
• Injury phaseR h• Recovery phase– Regeneration of necrotic tubules– Growth factors (EGF, IGF) accelerate recovery in experimental models not humans
– Other failed therapies: ANP, erythropoietin
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Potential Source of R ti C llPotential Source of R ti C llRegenerating CellsRegenerating Cells
Extrarenal cellsExtrarenal cellsSurviving tubular cellsSurviving tubular cells
Stem cells present within the kidneyStem cells present within the kidney
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Renal RegenerationRenal Regeneration
Poulsom R, Forbes SJ,
Grimm PC, Nickerson P,
Hodivala‐Dilke K, et al . J Pathol 2001; 195:229‐235
Grimm PC, Nickerson P, Jeffery J, et al . N Engl J Med 2001; 345:93‐97.
1989: Dedifferentiaton
2001: Extrarenal cells
2003: Cellular therapy
2004: Renal stem cells2004: Renal stem cells
2005: Dedifferentiaton
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ll l h f dCellular Therapy of Kidney Disease
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Cellular Therapy of Kidney DiseaseCellular Therapy of Kidney Disease• Acute kidney injury
Ischemia reperfusion– Ischemia reperfusion– CisplatinRhabdomyolysis– Rhabdomyolysis
• Kidney transplantationI d ti th– Induction therapy
– Subclinical rejectionDi b t• Diabetes
• SLEN h i d• Nephrotic syndrome– Doxorubicin– FSGS
• Genetic kidney diseases
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Mesenchymal Stem CellsMesenchymal Stem Cells
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Why MSCs?Why MSCs?• Migrate to site of injury• Release factors (paracrine and endocrine):
– Influence cell survival and proliferationM d l t i– Modulate immune response
– Anti‐inflammatory actions
• Pre‐clinical studies• Pre‐clinical studies• Safe in other diseases (Phase 1):
– Amyotrophic lateral sclerosisAmyotrophic lateral sclerosis– Multiple sclerosis– Stroke
C h di– Crohn disease– Acute graft‐vs‐host disease
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Cisplatin induced ARF
MSC
orHSCHSC
MSC saline HSC
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Mesenchymal Stem Cellsy
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Mode of Action: paracrine and endocrine
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Other Cell TherapiesOther Cell Therapies
• Embryonic stem cells (ESC) – risk of teratoma• Induced pluripotent stem cells (iPS) – can beInduced pluripotent stem cells (iPS) can be autologousE d h li l• Endothelial precursors
• Amniotic fluid stem cells• Adipose‐derived stem cellsAlso studies on engineering MSCs (e.g. overexpress CD44 to increase homing to the kidney.
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Ph 1 li i l t i l di ti t t hi h i kPhase 1 clinical trial: on-pump cardiac surgery patients at high risk of postop AKI treated with allogeneic MSC
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Kidney Transplantation
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• Primary outcome: incidence of bx proven AR and eGFR within first year• Secondary outcome: 1-year patient and graft survival and incidence of adverse eventsSecondary outcome: 1 year patient and graft survival and incidence of adverse events
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• MSC groups had faster renal recovery during first month
• DGF t diff t• DGF not different• AR not different at 1 year (better at
6 months with MSC)• Patient and graft survival similar• Less risk of opportunistic infection
in MSC donors
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6 HLA mismatched LD kidney recipients
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Other Kidney Diseases
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SLE CAN
i di id d d kMSC in 2 divided doses 1 week apartFollowed for 6 months
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Risks of Cellular TherapyRisks of Cellular Therapy
• Immunosuppression• Chromosomal abberationsChromosomal abberations• Neoplastic transformation• Pulmonary emboli• Lack of standardization of cell preparationsLack of standardization of cell preparations• Lack of efficacy
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4 Days
9 Days
12 Days
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Case PresentationCase Presentation
ld di b i d i d h• 58 year old diabetic man admitted to the ICU with an acute anterior MI
• Baseline creatinine 3.1 (diabetic nephropathy)• Persistent chest pain⇒ angiography andPersistent chest pain ⇒ angiography and emergent CABG
• Post op hypotensive (80/45) hypoxemic• Post‐op hypotensive (80/45), hypoxemic, wedge 31, CXR pulmonary edema, anuric with C 4 2 d K 6 0Cr 4.2 and K 6.0
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Evaluation and Treatment 2020• Preoperative genomic screen demonstrates increased susceptibility to AKI genotypesusceptibility to AKI genotype
• Serial perioperative biomarker screens demonstrate l ATNearly ATN
• Autologous mesenchymal stem cells ordered from Cell Bank and infused into suprarenal aorta
• Biomarker screen demonstrate good response to stem g pcells with all markers decreasing 12 hours following surgeryg y
• Housestaff attend History of Medicine lecture on use of serum creatinine to monitor kidney functionserum creatinine to monitor kidney function
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The End
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Acute Kidney Injury
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Cellular source of kidney regenerationCellular source of kidney regeneration
InjuryInjuryCells derived from surviving tubular cells
Cells derived from surviving tubular cells
Cell derived from stem cellsCell derived from stem cells
Injured renal tubuleInjured renal tubuleRenal tubuleRenal tubulestem cellsstem cells
Stem cellStem cell
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