Roslyn B. Mannon MD, FASN, FAST Professor of Medicine and Surgery - PowerPoint PPT Presentation

AKI in Kidney Transplantation: New Insights Roslyn B. Mannon MD, FASN, FAST Professor of Medicine and Surgery University of Alabama at Birmingham Birmingham AL, USA

Outline • Delayed graft function and impact on outcomes – Risk factors • Current status of human clinical trials – Mechanisms of injury • Failure to advance therapies

Delayed Graft Function: Feared and Avoided • Defined as at least one dialysis treatment post transplant • Incidence of 3% (Living donors) – 41.1% (DCD) [ AJKD 2010; 56:961 ] • Increased cost of hospitalization • Complex post management with dialysis • 41% increase in graft loss at mean of 3.2y and 38% increase in acute rejection [ NDT 2009; 24:1039 ] • Less robust kidney function post transplantation Buchanan et al. Jnl Nephrol Therapeutics 2011; S4:001

How Innate Cross Talks with Adaptive Immunity = Rejection…. • Classical complement activation • Recruitment of inflammatory cells (T, PMN, NK) • Endothelial and epithelial cell activation ie. adhesion molecules • Pro-coagulant effects with occlusion and vasoregulation • Highly inflammatory process of brain death with associated PAMPs and DAMPs

Risk Factors for DGF Mannon RB. Nephron 2018; 140:94

Strategies to Reduce DGF Donor Management Recipient • Volume expansion • Optimize perfusion • Reduce injury / inflammation – Clinical Stabilization • Dopamine • Immunosuppression selection • Temperature • Volume expansion Organ Procurement • Reduce injury / inflammation • Pressor support • Reduce CIT / WIT – Reduce injury & inflammation • Machine perfusion • Surgical technique

Role of Induction Therapy • Use of depletional induction may assist in recovery of renal function due to delayed institution of nephrotoxic CNIs (rATG induction than with the IL- 2RA agent daclizumab (DGF 31.5% vs 44.6%, P =.044) 1 – PREDICT- DGF study comparing induction with rATG vs basiliximab, both with delayed CNI initiation as per local practice, in patients at low immunological risk but at high risk for DGF (NCT02056938) terminated due to poor enrollment. • A meta- analysis of 6 randomized studies of rATG vs the IL- 2RA agent basiliximab, involving 853 patients, found no difference in the rate of DGF (RR 1.02 for rATG vs basiliximab; P=.93) 2 1 J Am Soc Nephrol . 2009;20:1385 – 1395 2 Transplant Proc . 2010;42:1667 – 1670

Thymoglobulin Induction Study Group • 278 randomized prospective trial of rATG ( total dose of 7.5 mg per kilogram ) versus basiliximab and triple immunosuppressive therapy for KTRs of deceased donor kidneys at risk for DGF and acute rejection Brennan DC et al. N Engl J Med 2006;355:1967.

Recipient Management: Volume Expansion of Recipient and DGF (Paired Kidneys) • Renal perfusion affects renal function (GFR = ∆ P x K uf ) • Impaired autoregulation after kidney injury • Lower ATN rates with high intraoperative PAP Group I Group II Outcomes ( > 4 Lts) ( < 2 Lts) p value N = 42 N = 42 ATN (No / %) 6 (14.3) 17 (40.5) < 0.001 UO (ml / hr – first 12 hours) 379 ± 227 149 ± 158 < 0.001 Transplantation 1983; 36: 455.

Recipient Management: Renal Dose DA • The utilization of infusion in recipients has not been associated with any significant benefit [Schnuelle et al. Clinical Transplant 2018; May 23] • No impact using fenoldopam (dopamine-1 receptor agonist) on DGF [McCune et al. Int Immunopharm 2005; 5: 85-92].

The Complexity of Cell Death in Acute Kidney Injury Pathways of apoptosis Regulated Necrosis Linkermann et al. JASN 2014;25:2689-2701 • Inhibition of apoptosis alone • Inhibition of necroptosis with caspase inhibitors (zVAD- through NEC-1 is only fmk, q-VD, and zIETD-fmk) partially effective has not been efficacious. – Their inhibition may affect – Ongoing DAMP release and other necessary cell death injury – Caspases are far – Delayed administration may downstream of apoptotic have no effect and thus pathways needed pre-emptively – Ongoing pathway, not just a one and done phenomena

Role of Mitigating AKI through Cell Death Pathways “Therefore , in view of the many subroutines of cell death in AKI, it is necessary to consider combination therapies that block multiple pathways of regulated cell death simultaneously or at different time points to ensure cell survival and renal function .”

Diannexin Treatment: encouraging preclinical data but not man • A biosynthesized homodimer of human annexin V, binds phosphatidylserine which is translocated to the cell surface during ATP depletion/injury T½ 6.5h • Reduced ischemic injury in rodent hepatic IRI and improved islet function post transplant [Am Jnl Transplant 2007; 7:2463] • Phase II study; 16 patients, dose escalation (part 1, safety); 42 randomized into three arms (control, diannexin low/mod), with better renal function and urine output compared to control. • Phase II/III (NCT01442337) terminated by sponsor decision Clinical Transplant 2013; 27(4): 484

Blocking Epithelial Apoptosis via P53 Silencing • Phase I: 40 KTRs (pts, 10/cohort, 12 centers) receiving DD Tx at increased risk for DGF randomized to receive either QPI-1002 or placebo in dose-escalation fashion pre-reperfusion. No dose limiting toxicity, DGF in 25% (N=10), ACR (N=2). • Phase II: 32 KTRs with escalating doses in a blinded fashion, primary endpoint was dialysis in first week. Suggestive. • A Phase 3, Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of QPI-1002 for Prevention of Delayed Graft Function in Recipients of a Donation After Brain Death Older Donor Kidney Transplant (ReGIFT; NCT02610296; N=634).

Extensive Toll Like Receptor Expression in the Kidney • Innate activation can be triggered by more than bacterial products such as: – HMGB1 – Heparin sulfate – Fibronectin – Heat Shock Proteins – Hyaluronan fragments RecAP, recombinant human chimeric alkaline phosphatase, • “Sterile inflammation” reduced TLR signaling via dephosphorylation. Adaptive phase IIa/b trial in critically ill adults with highly suspected bacterial sepsis and AKI (NCT02182440)

HMGB1 Release is Detected in the Urine and Serum of Deceased BD Donors URINE SERUM non-DGF DGF non-DGF DGF * 3 4 (fold non-DGF) (fold non-DGF) HMGB1 serum * HMGB1 urine 3 2 2 1 1 0 0 non-DGF DGF non-DGF DGF Zmijewska and Mannon, ATC 2017

Effectors of DAMPS PAMPS IRI DAMPS PAMPS DAMPS PAMPS c/o Rob Fairchild

Inhaled CO on Induce HO-1 Improves Recovery from DGF in Swine Air CO FDA hold on recipient inhalation phase II study Hanto et al. Am Jnl Transplant 10:2421; 2010

P-Selectin Blockade Gaber et al. Clin Transplant 2011: 25: 523 – 533 • YSPSL, a recombinant P-selectin rPSGL- Ig, efficiently binds P- and E-selectin and prevents initial PMN-adhesion and their sequestration in the injured tissues. • Phase IIa double-blind placebo controlled study in 59 human KTRs, dosed prior to reperfusion. Effect seen on renal function but not on dialysis- treated. • “Per Protocol DGF’’ ( PP-DGF) defined by meeting criteria in terms of clearance, SCR reduction or dialysis.

ICAM-1 Inhibition (enlimomab): Ineffective • In mice, monoclonal antibody against ICAM-1 was associated with improved allograft survival and reduced ischemic injury. • European Anti-ICAM-1 Renal Transplant Study (EARTS) – a randomized, double- blind, parallel-group, placebo-controlled study lasting 1 year and performed in 10 transplant centers in Europe with a total of 262 KTRs given either enlimomab or a placebo for 6 days plus cyclosporine/AZA/Pred. • No significant difference in first acute rejection at 3 months between the placebo and enlimomab groups (39% vs. 45%), or DGF (26% vs. 31%). Transplantation. 67(5):729-736, March 15, 1999.

ESA Treatment Has no Impact on DGF Higher systolic BP at 4 weeks post-transplantation Transplant Int . 2015;28:330 – 340.

Renal Sources of Complement neutrophils Epithelial cells fibroblasts C1, C4, C2 B, D, C3 Smooth muscle macrophages Mesangial cells

Complement Expression is Upregulated in Human Kidneys Post Reperfusion • Deceased-donor kidneys exhibited a significant increase in renal expression of complement genes • Post-transplantation biopsies from well-functioning, non-rejecting kidneys, regardless of donor source, also demonstrated a significant increase in complement expression • Functional correlates?? JASN 2009; 20:1839-1851

Complement Pathways and Sites of Intervention C1 INH Anti-C1S Ab ↓ pH ↑ NH4 +

Inhibition of C5 Protects Against IR Injury in the Mouse Transplantation 2003; 75:375-382

Anti-C5 Inhibition and DGF PROTECT ( NCT02145182) • Randomized double blind controlled study of 286 KTRs and two doses of eculizumab (enrollment goal 400) • The primary endpoint of incidence of DGF with a two-dose regimen of eculizumab compared with placebo did not reach statistical significance. • The incidence of DGF, death, graft loss, or loss to follow-up at 7 days post-transplant was 35.9% on treatment, compared to 41.7% for patients receiving placebo (p=0.398). – First 60 days following treatment, SAEs were lower for patients in the eculizumab group (44.4%) compared to control (54.1%).

Complement Pathways and Sites of Intervention C1 INH Anti-C1S Ab ↓ pH ↑ NH4 +