AKI to CKD Epidemiology and Predictive Models Lakhmir S. Chawla, MD

Overview Background Clinical Epidemiology Mechanism of Post-AKI to CKD Progression Trial Design

Study’s Conclusion

Coca et al, Kidney International, 2011

CON ARF ATN CKD Figure 2b

AKI Progression to CKD Pediatrics

49 studies, 3,476 patients From: Long-term Renal Prognosis of Diarrhea-Associated Hemolytic Uremic Syndrome:  A Systematic Review, Meta-analysis, and Meta-regression JAMA. 2003;290(10):1360-1370. doi:10.1001/jama.290.10.1360 Figure Legend: These studies had a higher proportion of patients with death or permanentend-stage renal disease (ESRD) at follow-up, explaining 10% of the between-studyvariability (P = .02), and a higher proportion ofpatients with a glomerular filtration rate (GFR) lower than 80 mL/min per1.73 m2, hypertension, or proteinuria at last follow-up, explaining15% of the between-study variability (P<.001).The area of each circle is proportional to the number of patients in eachstudy. Curves are best-fit lines from meta-regression. See "Methods" section.

Most conservative estimate 15/29 (59%) had at least one sign of renal injury (hyperfiltration, decr. GFR, or HTN) Most conservative estimate 15/126 (11.9%)

Fifty-two patients requiring RRT for AKI Thirteen available for 12-18 year follow-up 9/13 had one sign/symptom of CKD Majority of patients in both studies unavailable for follow-up

PICU Study BC Children’s prospective study AKI defined by AKIN criteria CKD = < 60 ml/min/1.73m2 CKD risk 60 to 90 ml/min/1.73m2 OR > 150 ml/min/1.73m2 Microalbuminuria BP > 95th percentile

Summary De novo AKI is associated with Incident CKD and ESRD Precise estimates of the incidence of CKD progression after AKI in children are lacking due to incomplete follow up Children who survive an episode of AKI requiring RRT deserve long-term follow up

AKI 2 million 1.7 million 1.5 million 300K 170K 300K 1 Billion 0 30d 60-90d 24 mo > 3 yrs 2 million 1.7 million 1.5 million AKI Survivors Round II AKI De novo and ACRF AKI Survivors Round III AKI Survivors Round I 300K 170K 300K 10-15% Mortality 10% ESRD 20% CKD 4

How does AKI progress to CKD? Host Predisposition: genetics / co-morbidities Nephron loss followed by glomerular hypertrophy Fibrosis and Maladaptive repair Vascular drop out as a consequence of endothelial injury

Wynn, Nature Med, 2010

Bechtel, Nature Medicine 16, 544–550 (2010) 5 azacytidine

Acute Kidney Injury Moderate Injury Severe Injury Normal Repair and Recovery Cell Cycle Arrest TGF-Beta1 Predominates Epigenetic Modification Sustained Myofibroblast Activation Interstitial Fibrosis

. Spurgeon K R et al. Am J Physiol Renal Physiol 2005;288:F568-F577 ©2005 by American Physiological Society

*Post-AKI vascular density does NOT return to normal *VEGF 121 given early after AKI preserves vascular density *High Na diet promotes fibrosis and progression to CKD

Can We Intervene? So what? Just like all AKI, if we don’t dialyze it now, we will have to dialyze it later Identification of patients at risk What are the risk factors?

Derivation Cohort – 5,351 -> Hospitalized patients with ATN or ARF, without CKD Validation Cohort - 11,589 -> Hospitalized patients with MI or Pneumonia and AKI - RIF

Derivation Cohort Validation Cohort Model 1 - Full C = 0.82, p < 0.0001 C = 0.81, p < 0.0001 Model 2 - Abbreviated Model 3 – Sentinel Events C = 0.77, p < 0.0001 C =0.82, p < 0.0001

One Year Survivors of AKI

Interventions Nephrologist (CKD clinic) See the patient? HTN control ACEi Low protein diet TGF-Beta inhibition VEGF promotion (early post-AKI) p53 inhibition (early post-AKI)

Summary Severity of AKI is associated with CKD progression in AKI survivors Decreased concentration of serum albumin is associated with progression to CKD Likely a marker if increased inflammation Breaking the vicious cycle of AKI to CKD to AKI to ESRD could have significant impacts on disease burden

Future Directions Beta-blocker for MI allegory Primary prevention study in AKI survivors to prevent progression to CKD Identify patients at risk Enroll, randomize 2 x 2 factorial design Interventions: BP control, RAAS inhibition, anti-inflammatory agents,