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

• Classical complement

activation

• Recruitment of inflammatory

cells (T, PMN, NK)

• Endothelial and epithelial

cell activation ie. adhesion molecules

• Pro-coagulant effects with
• cclusion and vasoregulation
• Highly inflammatory process
• f brain death with

associated PAMPs and DAMPs

How Innate Cross Talks with Adaptive Immunity = Rejection….

Risk Factors for DGF

Mannon RB. Nephron 2018; 140:94

Strategies to Reduce DGF

Donor Management

• Volume expansion
• Optimize perfusion
• Reduce injury / inflammation
• Dopamine
• Temperature

Organ Procurement

• Reduce injury / inflammation
• Reduce CIT / WIT
• Machine perfusion
• Surgical technique

Recipient

–Clinical Stabilization

• Immunosuppression selection
• Volume expansion
• Pressor support

–Reduce injury & inflammation

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

1J Am Soc Nephrol. 2009;20:1385–1395 2Transplant 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.

Outcomes Group I ( > 4 Lts) N = 42 Group II ( < 2 Lts) N = 42 p value 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.

• Renal perfusion affects renal function (GFR = ∆ P x Kuf)
• Impaired autoregulation after kidney injury
• Lower ATN rates with high intraoperative PAP

Recipient Management: Volume Expansion of Recipient and DGF (Paired Kidneys)

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].

Pathways of apoptosis Regulated Necrosis

Linkermann et al. JASN 2014;25:2689-2701

The Complexity of Cell Death in Acute Kidney Injury

• Inhibition of apoptosis alone

with caspase inhibitors (zVAD- fmk, q-VD, and zIETD-fmk) has not been efficacious. – Their inhibition may affect

• ther necessary cell death

– Caspases are far downstream of apoptotic pathways – Ongoing pathway, not just a

• ne and done phenomena
• Inhibition of necroptosis

through NEC-1 is only partially effective – Ongoing DAMP release and injury – Delayed administration may have no effect and thus needed pre-emptively

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

• f 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

• “Sterile inflammation”

RecAP, recombinant human chimeric alkaline phosphatase, 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

1 2 3 4

non-DGF DGF

URINE HMGB1 urine (fold non-DGF)

non-DGF DGF

1 2 3

SERUM HMGB1 serum (fold non-DGF)

non-DGF DGF

non-DGF DGF * *

Zmijewska and Mannon, ATC 2017

Effectors of IRI

c/o Rob Fairchild DAMPS PAMPS DAMPS PAMPS DAMPS PAMPS

Hanto et al. Am Jnl Transplant 10:2421; 2010

Inhaled CO on Induce HO-1 Improves Recovery from DGF in Swine

Air CO

FDA hold on recipient inhalation phase II study

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

• n 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.

Transplant Int. 2015;28:330–340.

ESA Treatment Has no Impact on DGF

Higher systolic BP at 4 weeks post-transplantation

Renal Sources of Complement

Epithelial cells Smooth muscle Mesangial cells macrophages neutrophils fibroblasts C1, C4, C2 B, D, C3

Complement Expression is Upregulated in Human Kidneys Post Reperfusion

JASN 2009; 20:1839-1851

• 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??

Complement Pathways and Sites of Intervention

↓pH ↑NH4+

C1 INH Anti-C1S Ab

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

↓pH ↑NH4+

C1 INH Anti-C1S Ab

C1N Treatment

Seventy deceased donor KTRs at risk for DGF were randomized to receive C1INH 50 U/kg (#35) or placebo (#35) intraoperatively and at 24 hours.

– The primary end point was need for hemodialysis during the first week post- transplant. – No reduction in dialysis in week 1. – Significantly fewer sessions weeks 2-4 – Better eGFR over year with treatment

Am J Transplant 2018 Apr 10. doi: 10.1111/ajt.14767.

Hepatocyte Mimetic Trial (BB3)

• Hepatocyte growth factor/scatter factor (HGF/SF) treatment is

associated with improved tissue viability and dysfunction in the setting

• f animal models of organ ischemia.
• A Multicenter, Prospective, Double-Blind, Randomized, Placebo-

Controlled, Phase 3 Study of BB3 to Reduce the Severity of Delayed Graft Function in Recipients of a Deceased Donor Kidney (NCT02474667) – Randomized double blind, placebo-control, dosed mimetic used post- transplantation – “Poor” renal function in the first 24 hours post-transplantation based

• n an average UO < 50 mL/hour over any 8 consecutive hours, to

maximize the likelihood that the patient requires dialysis within the first 7 days post-transplant

Challenges in DGF/IRI Trials

O’Neill S, et al. Expert Opin Drug Discov. 2015;10:753–62

• Despite extensive experimental investigation there is currently

no active pharmacological agent used during transplantation to reduce IRI

• Translational disconnect between the preclinical models used

and the typical clinical problems encountered in transplant recipients

• The few clinical trials conducted to date have included small

numbers of renal transplant recipients, used heterogeneous early endpoints and tested single agents in isolation

• Scientific knowledge of the complexity of IRI is rapidly evolving

and new treatments are expected to emerge

FDA, CDER. Delayed Graft Function in Kidney Transplantation: Developing Drugs for Prevention: Guidance for Industry. UDHHS, March 2017

• Trials should be superiority trials in which active treatment is compared with placebo
• Clinical trial population for efficacy trials should include male and female de novo

kidney transplant recipients, representative of a US patient population, including race, age, sex, and other baseline characteristics

• Type of donors, preferably graded using new Kidney Allocation System should be

specified in protocol

• Consideration should be given to stratifying study enrollment based on:
• Study center, type of induction treatment (if more than one)
• Organ type and organ preservation method (highly recommended)
• Enrichment strategies can be used to select the study population at higher risk for

developing DGF compared to overall kidney transplant recipient population

FDA Guidance: Efficacy Considerations

• Short-term assessment or composite endpoint

– Common definition of DGF (ie, requirement for hemodialysis within first 7 days posttransplantation) can be used as primary endpoint; other definitions supported by literature also can be proposed – Alternative to DGF occurrence binary endpoint: DGF severity scoring systems can be proposed

• Number of hemodialysis sessions required until recovery of renal function; time to recovery of renal function

after diagnosis of DGF

• If DGF severity scoring endpoint is primary endpoint, justification for clinical significance and relevance of

the proposed score difference should be provided

– Information on hemodialysis sessions after Day 7 until posttransplant day 30 (regardless of reason) should be collected to evaluate durability of treatment

• Short-term composite endpoint using slow graft function (SGF) and functional DGF

(fDGF)

– Protocol should include specific definition of SGF and fDGF – Use of scoring systems for these outcomes should be specified, with prospectively defined difference in scores justified as clinically meaningful

Designing New Clinical Trials: Delayed Graft Function Risk Profiling

Irish WD. Am Jnl Transplant 2010; 10:2279

• Recently validated by other

investigators [Nephrol Dial

Transplant (2018) 33: 1259–1268].

• Prediction based on 25% DGF

prevalence

• Impact of pump perfusion?
• Impact of higher prevalence

due to longer CIT?

• Enrichment trials using

additional clinical metrics

Summary/Conclusions

• DGF is common after kidney transplantation, an inflammatory

injury mediated by the innate and adaptive immune system, with both acute and long term impacts of DGF on patient survival and graft function and survival.

• A lot of accrued preclinical data in recipient animal models hasn’t

translated into success in man.

• Promising human therapies include proximal complement inhibition,

and still pending evaluation of results using anti-apoptotic therapy.

• Improved study design might enhance clinical innovation and

attraction to the field.

Acknowledgments

CTOT Consortia

– Flavio Vincenti – Peter Heeger – Robert Fairchild – Ken Newell/Peter Stock – Nancy Bridges – David Ikle (Rho) – Brian Armstong (Rho)

DeKAF Consortia

– Arthur Matas – Ajay Israni – Pam Jacobson – Robert Gaston – Joseph Grande – Lawrence Hunsicker – Bert Kasiske – Michael Cecka – Fernando Cosio

Mannon Lab

– Anna Zmijewska – Melissa Oliver – Jianguo Chen – Michael Seifert – Miguel Melendez-Ferro – Audrey Ang – Ellen Kasik – Miriam Bernard

STAR

Anat Tambur Peter Nickerson Sandy Feng Annette Jackson Medhat Askar Ken Newell Michael Mengel Stuart Knectle

Past Lab Members

– Orlena Cheng—NIDDK – Raphael Thullier—INSERM – Paolo Cravedi—Mt. Sinai – Nora Fransceschini—UNC