Long-term survival and morbidity after Acute Kidney Injury

Claire Stigare
Karolinska Sjukhuset Stockholm
Claire Stigare SFAI 2017
Long-term survival and morbidity after
Acute Kidney Injury

Conflicts of interest
• Lecture fee and travel expenses from Gambro 2013
• Our research group has received a grant from Baxter International

Long-term survival
Morbidity
How can we improve long-term outcome?

S: 70 yr ♀. Community acquired pneumonia, sepsis & AKI. ICU day 6
B: Hypertension, tablet controlled diabetes,
Baseline creatinine 90 (weight 65kg)
GFR = ca 55ml/min/ 1.73m3
Status: A. Free airway & conscious
B. Extubated day 5, NIV.
C. Vasopressor free.
Renal: CRRT for 4 days now ceased.
Diuresis with loop diuretic,
Creatinine 150 (max 345umol/l), Urea 16 (max 28mmol/l), cystatin C 1,9 mg/l.

• Chance of being alive at 1 & 5 years?
• What will happen to her renal function and how will we know?
• Chances of developing CKD or ESRD?
• Long-term risk of other organ dysfunctions?

Mortality after AKI

Rimes-Stigare et al, Critical care 2015
Swedish Intensive Care registry 103,000 patients

One year Mortality in ICU patients with AKI
Study Year N Setting In-hospital or
30-day
mortality %
One year mortality
Bagshaw 2005 240 ICU 59 63.8
Wong 2005 102 Liver transplant 69 72
Carl 2010 130 ICU 58 76.4
Long 2013 3686 Hospital 48
Poukkanen 2015 774 ICU 26.5 39.8
Eriksson 2015 103 Trauma 17.5 26.2
Survival in 90 day survivors
Study Year N Setting Follow-up time
(Years)
Mortality
%
Gammelager 2012 4793 Mixed ICU 1 20-23.2
FINNAKI (Mildh) 2016 2336 Mixed ICU 3 23.5

3-5 year Mortality
Study Year No of
patients
Setting In-hospital or
30-day
mortality %
Follow-up
time (Years)
Total Mortality
%
Triverio 2009 206 ICU 53 3 67
Landoni 2006 126 Cardiac Surgery 67 3,5 76.2
RENAL (Gallagher) 2014 1464 ICU 4 63
Korkelia 2000 62 ICU 45 5 64.5
Morgera (93-98) 2002 979 ICU 69 5 84.5
Luckraz 2005 98 Cardiac + CRRT 42 5 48
Ahlström 2005 703 ICU 41 5 69.5
SIR (Rimes-Stigare) 2015 5273 Mixed ICUs 38.1 5 61.8

AKI mortality temporal improvement
Long et al. Nephrology. 2016
• Hospitalised AKI patients
• One-year survival increased from 47% in 1993-1997 to
57% in 2008-2013

Morbidity
Renal dysfunction

Acute Kidney Disease (AKD)
Damage/ loss of function 7 - 90 days after AKI.
Grade change from baseline Creatinine.
Chronic Kidney Disease.(CKD)
Structural /functional abnormality lasting
> 90 days. GFR <60ml/min/1.73m2
End Stage Renal Disease (ESRD)
Advanced CKD (grade 5),
GFR< 15ml/min/1.73m2,
or dialysis or transplant Chawla, L. S. et al. (2017) (ADQI).

Factors which increase risk of CKD
& maladaptive repair after AKI
• Hypoxia
• Age
• Pre-existing renal dysfunction
• Hypertension
• Diabetes

Acute Kidney Disease
AKD grade N %
AKD grade 1-3 47 18.7
Totalt 252 100
From submitted manuscript Rimes-Stigare et al 2017.
3 month follow-up of 252 ICU patients with AKI from Karolinska Hospital, Stockholm

Incidence of CKD after AKI.
Clinical studies
CKD between 20-44% Bucaloiu et al 2012,
Amdur et al 2009
Ponce et al 2016
• Coca 2011 meta-analysis-15 clinical studies.
AKI survivors higher risks for developing CKD
Pooled incidence CKD 25.8 per 100 person-years
Hazard ratio 8.8

Author Year Setting N Renal
recovery
definition
Time Recovery
(%)
Macedo 2012 Brazil 84 GFR >60 18 months 64
Ponce 2016 AKI grade
III
3500 36 months 56.7%
Long 2016 Iceland 25,000 Creatinine
<1.5*baseli
ne
(up to 10
years)
AKI I 88%
AKI III
44%
Ali 2007 Scotland >500000 Creatinine
<150umol/
l/ men
<130mmol
/l women
90 days 68%
Schiffl 2008 Germany.
RRT
survivors
226 GFR >60 1 year
5 years
85%
90%
Recovery

Group Probability of ESRD (%)
1 year 5 year
No renal disease 0.08 0.30
AKI 2.03 3.88
Chronic only 9.13 21.09
Acute on chronic 19.71 25.45
Crude estimates of likelihood of developing ESRD
Rimes-Stigare
Critical Care 2015 19:383

Metanalysis
Coca Kidney Int. 2012.
AKI with prior CKD associated with 4-5x risk of ESRD versus
AKI without prior CKD Ishani 2009 and Lafrance 2010

Long-term risk of remote organs
dysfunction
associated with AKI

• Cardio-renal syndromes
Hypertension
Ischemic heart disease
Heart failure
Cardiac deaths
Gammelager 2014
James 2011
Wu 2014

Respiratory
Pulmonary renal syndrome AKI ⇄ COPD
Shiao Critical Care 2015

Neurological
– Stroke
– Dementia
Wu 2014
Gammelager 2014

Immunomodulation
Increased long-term risk of:
• Sepsis
• TB infection
• Cancer:
Gasto-intestinal, genitourinary & respiratory tract.
Lai 2013, Clarke 2014, Doyle 2006 , Wu 2013, Chao 2014

Gastro-intestinal
GI bleeds
Wu 2014

Skeletal system
Fractures
Wang 2014 JBMR

AKI affects:
• Electrolyte & volume homeostasis
• Endothelial function
• Metabolism & endocrine function, bone mineralisation.
• Iron homeostasis
• Immunity: Pro-inflammatory response, cytokine homeostasis, leukocyte
trafficking , alter T cell production
• Epigenetic modifications

What can we do to improve
mortality and morbidity?
• Prevention
• Treatment- Optimisation of fluid balance
- Timing, mode, dose of CRRT
• Intervention post ICU? Follow-up

Do we follow patients ?
• Structured follow-up programme lacking in Sweden.
• Incidence of nephrological follow-up:
8,5% USA - Siew et al 2012,
17% Canada - Silver et al 2015.
12% UK -Kirwan, Prowle et al 2015

United States Renal Data System.
Annual report 2013 . Chapter 6.

• Harel: Dialysis requiring AKI patients early nephrological follow-up versus
no follow-up 8,4 versus 10.6 per 100-patient years, HR 0,76.
• Silver 2012: Nephrology referral led to intervention in 70% of patients.

How could Follow-up improve outcome?
Medication review- removal of nephrotoxins
Blood pressure control
Glucose control
Treatment of anemia
Control of electrolytes, vitamins, hormones,
Dietary and lifestyle advice

Summary: long-term outcome after AKI
70 year old lady. pneumonia, sepsis & AKI.
Alive one year? five years?
≈ 50% at one year ≈30% at 5 years
Will we know what her renal function is?
???
Chances of CKD or ESRD?
>30% risk of CKD >4% risk of ESRD at 5 years
Increase long-term risk of other organ dysfunctions?
Yes!

Please ensure AKI patients are
followed-up.
Thank you

CKD
• Risk of CKD after AKI
• Bucaloiu HR 1.9. Pensylvannia: Propensity matching 1610 AKI
matched with 3000 controls The incident rates for CKD were 28.1 and
13.1/1000 person years in the AKI and control groups, respectively;
the corresponding CKD rate ratio (95% CI) was 2.14 (1.96,
2.43), P<0.0001.

Cardiac
Neurological
Respiratory
Immunomodulation
-Increased infection & neoplasm risk
Gastro-intestinal
Loco-motor

Risk of ESRD if pre-existing CKD or
Acute on chronic disease (AOC)
• Underlying risk for CKD ->ESRD in community = 4-6/1000 person/year
Dalrymple et al J Gen Intern Med 2011
Mahmoodi et al Lancet 2012
• SIR study. Incidence rate of ESRD : CKD 69/1000 person years (x10)
AOC 138/1000 person years (x20)
Risk of ESRD versus ICU controls with no renal disease
Adjusted IRR CKD =96.4, AOC =259

Type of AKI
• Trauma
• 1-year (26.2% vs. 7.1%) mortality
• J Trauma Acute Care Surg. 2015 Sep;79(3):407-12. doi:
10.1097/TA.0000000000000727.
• Acute kidney injury following severe trauma: Risk factors and long-
term outcome.
• Eriksson M1, Brattström O, Mårtensson J, Larsson E, Oldner A.
• Cardiac
• sepsis

Survival is increasing over time
• One-year survival of H-AKI patients improved from 47% in 1993-1997 to
57% in 2008-2013 and the adjusted hazard ratio for mortality improved,
compared to the first 5-year period, 0.85 (0.81-0.89), 0.67 (0.64-0.71), and
0.57 (0.53-0.60) for each subsequent 5-year interval. Recovery of renal
function was achieved in 88%, 58% and 44% of patients in Stages 1, 2 and
3, respectively, improving with time.
• Nephrology (Carlton). 2016 Dec;21(12):1027-1033. doi:
10.1111/nep.12698.
• Improved long-term survival and renal recovery after acute kidney injury
in hospitalized patients: A 20 year experience.
• Long TE1,2, Sigurdsson MI3,4, Sigurdsson GH1,3, Indridason OS2,5.

Long-term remote organ consequences following acute kidney injury. Chih-Chung et al Critical Care 201519:438
Outcomes
Hazard ratio (95 % Confidence interval)
References and details
No-AKI Recovery-AKI Non-recovery AKI
Coronary event Reference 1.67 (1.36–2.04)a –
Wu et al. [12]; n = 4,869x2b; mean
f/u: 3.31 yrs
Upper gastrointestinal
bleeding
Reference 1.30 (1.14–1.48)a ESRD after AKI recovery 2.31
(1.92–2.79)a
Wu et al. [87]; n–4,565x2b; median
f/u: 2.33 yrs
Incident Stroke Reference 1.25 (1.10–1.65)a –
Wu et al. [60]; n = 4,315x2b; median
f/u: 3.36 yrs
Severe sepsis Reference 1.58 (1.15–2.16)a ESRD after AKI recovery 1.99
(1.71–2.31)a
Lai et al. [103]; n = 2,983 + 11,932b;
median f/u: 3.96 yrs
Active tuberculosis Reference 3.84 (2.07–7.10)a 6.39 (3.57–11.45)a Wu et al. [68]; n = 2,909 + 11,636b;
mean f/u: 3.6 yrs
Malignancy 0.66 (0.45–0.98)c Reference 1.49 (1.02–2.03)c Chao et al. [100]; n = 623x3b; mean
f/u: 3.7 yrs
Bone fracture Reference 6.59 (2.45–17.73)a –
Wang et al. [92]; n = 448 + 1,792b;
mean f/u: 3.9 yrs.
All the studies defined renal recovery by independence from RRT are population-based study based on Taiwan National Health Insurance Research Database. AKI defined by RRT initiation, while recovery defined
by withdraw from RRT
aStatistical significancy comparing with no-AKI group bMatched patients cStatistical significancy comparing with recovery-AKI group dStatistical significancy comparing with non-
recoveryAKI group

Macedo 84 AKI survivors four recovery patterns, 36% had creatinine estimated GFR less than 60 mL/min/1.73m2 at 18
months (5). Macedo PloS one 2012; 7:e36388
Ponce creatinine AKI grade 3 500 patients 43.3% with CKD at 36 months (6). Ponce D,. Nephrology (Carlton) 2016;
21:327–334
Islandic register over 25,000 patients in-hospital AKI, renal recovery (< 1.5 times baseline creatinine) 88% to 44% in AKI
grade 1-3(21). Long TE, Nephrology (Carlton) 2016; 21:1027–1033
Half a million people 68% of patients returned to a “threshold level” (creatinine<150umol/l for men, < 130umol/L in
women)(22). Scottish Ali T, Khan I J Am Soc Nephrol 2007; 18:1292–1298
Schiffl 15% of patients with severe AKI to have creatinine eGFR less than 60 mL/min/1.73m2 at one year.. Nephrol Dial
Transplant 2008; 23:2235–2241 German

Future therapies
• Antifibrotic therapies
- G2/M arrested cells
- modulation of Growth factors ,
- modulation of immune mediators
Factors modulating pericyte function

Nephrology
• certain patients, such as those with more severe AKI, seeing a
nephrologist within 90 days of hospital discharge may improve
survival. Harel and colleagues42 used population-based data from
Ontario, Canada, to demonstrate lower all-cause mortality in patients
who recovered from dialysis-requiring AKI compared with propensity
score-matched AKI patients without such follow-up (HR 0.76, 95% CI
0.62-0.93).

3-month follow-up of 294 ICU AKI patients from
Karolinska Hospital, Stockholm.
KDOQI
CKD stages
N = 201
GFR formula (%)
Lund-Malmö
Creatinine based
CKD-EPI
Cystatin C based
CKD-EPI combined
Creatinine & Cystatin C based
Groups 3,4&5 = CKD
GFR under 60
30.8 63.7 42.2
From submitted manuscript Rimes-Stigare et al 2017.

• Small rises in creatinine associated with increased mortality. (Lassnigg 2004, Cork 2015)
• Mortality AKI versus non AKI hospitilised patients ( HR 2.0, 95% CI 1.3–3.1) Coca 2011
• Mortality risk is linearly associated with AKI grade
Rimes-Stigare 2017

Long-term survival and morbidity after Acute Kidney Injury

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