Acute Kidney Injury: Prevention is the Key! Caribbean Institute of Nephrology 10th Annual Conference on Nephrology & Hypertension Acute Kidney Injury: Prevention is the Key! Michael Heung MD MS Associate Chief, Division of Nephrology University of Michigan mheung@med.umich.edu @keepingitrenal

Disclosures I have no relevant financial disclosures or conflicts of interest to report.

Outline/Learning Objectives Describe impact of AKI on overall kidney disease burden Describe approaches to AKI prevention Discuss possible paths forward

AKI Epidemiology and Outcomes Meta-analysis of large cohort studies, focusing on those using KDIGO definition for AKI (n=3,585,911) Pooled incidence 21.6% in hospitalized adults Mortality rate declined over study period (2004-12) All-Cause Mortality Odds of mortality compared to no AKI Susantitaphong et al, CJASN 2013;8:1482-93

Pooled AKI incidence rates by world regions Susantitaphong et al, CJASN 2013;8:1482-93

AKI as a Pathway to CKD Non-Recovery ESRD Severe AKI Full Recovery Traditional view: - AKI could lead to ESRD or CKD directly through non-recovery or partial recovery respectively - However, “full” renal recovery was considered a fortuitous and benign event Partial recovery CKD

Long-Term Renal Risk After AKI Heterogeneity among studies, including definition of AKI Emphasis on severe AKI Limited data by AKI severity Development of CKD: Pooled HR 8.82 (3.05-25.48) 2012 Meta-analysis illustrating the link between AKI and subsequent CKD and ESRD Key points are on the slide: Limitations include heterogeneity in how AKI was defined across different studies, plus more emphasis on severe AKI Many studies used administrative data, so unable to compare by AKI severity Nonetheless, you can see the significant increased risk for both CKD and ESRD after an episode of AKI Development of ESRD: Pooled HR 3.10 (1.91-5.03) Coca et al, KI 2012;81:442-8

Dialysis-Requiring AKI Impact of “Mild” AKI Analysis of 104,764 hospitalizations in VA (2011) Relative Risk of CKD 1 Year After Hospitalization Reference group is no AKI Adjusted model This slide brings the conversation back to the connection between AKI and later CKD. In the VA, we saw a graded increased risk for CKD with worsening severity of AKI. But importantly, even mild (stage 1) AKI was associated with nearly double the risk of developing CKD compared to patients who did not have AKI. Above are adjusted relative risk ratios from modified Poisson regression. Model included: age, race, sex, pre-admission diabetes and hypertension, sepsis, mechanical ventilation, baseline eGFR. Stage 1 AKI Stage 2 AKI Stage 3 AKI (no dialysis) Dialysis-Requiring AKI Heung et al, AJKD 2016;67:742-52

AKI Recovery Pattern Matters Even transient (“benign”) AKI is associated with increased risk for subsequent CKD Cause or association – does it matter? Importance of recognition and potential for secondary prevention Follow-up data from previous slide, now incorporating novel aspect of “recovery pattern”. Key point is that even mild, transient AKI (i.e. “prerenal azotemia”) appears to be important. One can argue the causation vs association relationship, but regardless the relationship is there. This argues for increased awareness of longterm risk after AKI and therefore the need for follow-up (which is a segway to the next few slides). Risk of CKD 1 Year After Discharge Heung et al, AJKD 2016;67:742-52

Updated Paradigm: AKI and Renal Risk Non-Recovery ESRD Primary Prevention Secondary Prevention Any AKI Recovery Secondary Prevention Update paradigm: Even AKI with recovery puts patients at risk for longterm CKD and ESRD Partial recovery CKD

Challenges in Primary Prevention Balancing nephrotoxin exposure versus clinical need  risk of “renalism” Community-acquired AKI Lack of high-level evidence-basis for specific interventions Lack of nephrology involvement at prevention stage

Secondary Prevention Prevention of mild AKI progressing to more severe AKI Prevention of development/progression of CKD after AKI recovery Promoting renal function recovery after severe AKI

“PrevAKI” Study 72hrs post-op Meersch (2017): Single-center RCT (n=276) of pts undergoing cardiac surgery identified as high risk by [TIMP-2*IGFBP7] >0.3 at 4hrs post-CPB Randomized to usual care versus “bundled care” 2 reasons to bring this up: First study to show potential impact difference of biomarkers for AKI  how to incorporate into practice, perhaps? Example of protocolized management having clinical benefit Akin to what’s been shown in sepsis? Meersch, Int Care Med 2017, epub Jan 21

PrevAKI “Bundle” Avoidance of nephrotoxins Attempt to avoid radiocontrast Discontinuation of ACEI/ARB for 48hrs post-op Close monitoring of SCr and UOP Avoidance of hyperglycemia Close hemodynamic monitoring Draw analogy to impact of bundling on sepsis outcomes (EGDT) Meersch, Int Care Med 2017, epub Jan 21

BigpAK Study Gocze (2017): Single-center RCT in patients undergoing major (>4hr) non-cardiac surgery (n=121) High risk cohort ([TIMP2*IGFBP7]>0.3) Any AKI Stage 2/3 AKI ICU LOS P=0.035 48.0% 27.1% 19.7% 6.7% Gocze Ann Surg 2017, epub Aug 29

BigpAK “Bundle” Emphasis on volume therapy (balanced solutions) based on CVP<10 and evidence of fluid-responsiveness (SVV>10%, IVC<2cm, response to passive leg raise, response to 200mL fluid challenge) Target MAP >65mmHg Key difference: Nephrology consultation at time of randomization Monitoring of nephrotoxins, medication adjustment My new favorite study! - Proof that nephrologists change outcomes???

Preventing Progression to CKD Recognition of AKI as a prolonged inflammatory state Bao (2014): Use of lithium to promote renal recovery post-AKI in micr models Inhibitor of glycogen synthase kinase 3ß Bao JASN 2014;25:488-500

Retrospective cohort of AKI patients requiring outpatient dialysis (n=100) At 90 days follow-up: 43% recovered off-RRT, 48% ESRD N= 43 38 13 2 N = 13 55 11 21 Hemodial Int 2017; epub Mar 13

Predictors of Renal Recovery Variable Recovery (n=43) Non-Recovery (n=57) P-value Diabetes Mellitus 25.6% 43.9% 0.059 CHF 42.1% 0.086 Charlson index 2.3 (1.7) 3.1 (1.8) 0.041 Baseline eGFR 73.6 (28.8) 51.6 (28.6) <0.001 Initial RRT modality CRRT 48.8% 15.8% UOP at discharge 684 (733) 279 (416) 0.002 No differences in laboratory parameters (Cr, BUN, albumin) at time of admission or RRT initiation No differences in duration of inpatient RRT requirement No differences in fluid overload

Outpatient Hemodialysis Care Focusing on 1st week of outpatient dialysis: Variable Recovery (n=43) Non-Recovery (n=57) P-value Total fluid removal (L) 4.1 (2.9) 5.3 (2.7) 0.037 Ultrafiltration rate (mL/kg/hr) 4.7 (3.2) 6.0 (3.2) 0.041 Hypotension (>3 episodes of SBP<90) 9.3% 24.6% 0.049

What About Peritoneal Dialysis? Potential advantages: Preservation of residual renal function/promotion of renal recovery Avoidance of catheter-related bloodstream infections Less inflammation and hemodynamic instability compared to standard HD Moist (JASN 2000): In new ESRD patients, compared to HD, PD associated with lower loss of residual renal function (adj OR 0.35, p=0.0001)

Potential Role of PD? Theoretical benefit over HD for renal function recovery At present, not enough evidence to clearly support a role Testable hypothesis: Early conversion to PD around hospital discharge may increase likelihood of renal function recovery Compared to standard IHD? Compared to daily extended HD? Potential pitfalls: Training of an acute patient population New urgent start PD programs, or assisted PD Follow-up and monitoring of recovery Metabolic effects (glucose) Peritonitis risk (fluid overload)

Summary AKI occurs commonly among hospitalized patients, and contributes significantly to overall kidney disease burden At present, prevention of AKI remains the best approach to curbing the impact of this syndrome Primary Secondary

Thank you!