Transcript Acute Kidney Injury on Chronic Kidney Disease

Acute Kidney Injury on
Chronic Kidney Disease
Maria Ferris, MD, MPH. PhD
Associate Professor
Director of the Pediatric Dialysis and Transplant Services
UNC Kidney Center, Chapel Hill, NC, USA
Akash and his fan club
The Bunchman Bunch
A Call at the 11th hour…
• A 10 y.o. male, SCr of 353.6 µmol/L (4 mg/dl),
has oliguria unresponsive to furosemide
A Call at the 11th hour…
• A 10 y.o. male, SCr of 353.6 µmol/L (4 mg/dl),
has oliguria unresponsive to furosemide
• Oh, and your partner treats this patient for
CKD stage 3A (eGFR 45–59 mL/min/1.73 m2)
due to obstructive uropathy…
A Call at the 11th hour…
• A 10 y.o. male, SCr of 353.6 µmol/L (4 mg/dl),
has oliguria unresponsive to furosemide
• Oh, and your partner treats this patient for
CKD stage 3A (eGFR 45–59 mL/min/1.73 m2)
due to obstructive uropathy…
• But what if this boy had not been diagnosed
yet as having chronic kidney disease?
Acute Kidney Injury (AKI) on
Chronic Kidney Disease (CKD)
• CKD can be “silent” until the later stages
• AKI on CKD can be difficult to distinguish if the
patient has not been diagnosed as having CKD
• Information that can help you:
– Past medical history: Current age, short stature
– Past school performance (cognition impairment)
– Anemia, enuresis, deafness
– Metabolic bone disease, ↑Parathyroid hormone
– Renal ultrasound
Diagnosis of
CKD/ESKD
varies by age
(USRDS)
Ferris M and Mahan J
Sem. in Nephrology 2009:29, 4; 435
Measuring and
estimating glomerular
filtration rate in
transplant
eGFR Equations in Pediatric Transplant
Name
Formula expressed in ml/min/1.73m2
PCr-based formulas
Bedside Schwartz
K×height (cm) /PCr mg/dL, with K=0.413
Schwartz–Lyon
K×height (cm)/PCr mg/dL, with K=0.413 in boys >13 yr and K=0.367 in others
CystC-based formulas
Hoek
−4.32+(80.35/CystC)
Filler
Log(eGFR)=1.962+[1.123×log(1/CystC)]
Combined formulas
CKiD 2012
39.8 × (ht in meters)/ PCr mg/dL)0.456×(1.8/CystC mg/L)0.418×(30/BUN
mg/dL)0.079 × (1.076)male× (height in meters/1.4)0.179
Zappitelli
[43.82×e0.003×height (cm)] / [Cys mg/L 0.635]×[PCr mg/dL0.547]
In kidney transplant recipients: × 1.165
In patients with spina bifida: 1.57 × PCr mg/dL 0.925
Males 55% Median age 11.5 y.o.a. (7.7–15.1) Median creatinine (mg/dl) 0.87 (0.67–1.20)
De Souza, Cochat et al CJASN 2015 Jan 23. pii: CJN.0630061
Accuracy in Measured or Estimated GFR
in Pediatric Kidney Transplantation
FORMULA
mGFR ≥90
ml/min/1.73m2
n= 9 pats with
23 measurements
mGFR≥60 and <90
ml/min/1.73 m2
n=22 pats with
91 measurements
Zappitelli
P 30: 30% accuracy
P30 values >80%.
mGFR<60 ml/min/1.73
m2 n=42 pats with
85 measurements
(95% CI 87%, 100%)
Schwartz
P10: 10% accuracy
P30: 56% (95% CI 32,72%)
CKiD 2012
P10 50% (95% CI, 34-55%)
P10 45% (95% CI, 34-55%)
P30 90% (95% CI 84%, 97%)
SchwartzLyon
P10: 43% (95% CI, 34-45%)
P30: 91% (95% CI 86%, 98%)
P10: 43% (95% CI, 34-45%)
P30: 91% (95% CI 86%, 98%)
All equations except Hoek and Filler had AUCs significantly >90% in
discriminating patients with renal dysfunction at various CKD stages
De Souza, Cochat et al CJASN 2015 Jan 23
Accuracy in Measured or Estimated GFR
in Pediatric Kidney Transplantation
In kidney transplant recipients, the CKiD
2012 formula had the best performance
at mGFR <90 ml/min per 1.73 m2
Cystatin C-based formulas were not
superior to Creatinine-based formulas
De Souza, Cochat et al CJASN 2015 Jan 23. pii: CJN.0630061
Medications and GFR measures
• Plasma Cr– or cystatin C–based GFR formulas
may underperform as corticosteroids and
trimethoprim may affect Cr concentration
• Calcineurin inhibitors may also affect Cystatin
C concentration
Acute Kidney Injury at the
Microscopic Level
Tubules and interstitium interact to produce
tubulointerstitial fibrosis in AKI
Normal tubule
interstitium
Early tubular
fibrosis
Manjeri A. Venkatachalam et al. JASN doi:10.1681/ASN.2015
Failed differentiation of proximal tubules
regenerating after AKI leads to
development of the atrophic abnormally
signalling profibrotic tubule phenotype
Venkatachalam et al. JASN doi:10.1681/ASN.2015
AKI Injured kidney tissue heals by fibrosis that does not extend to
involve previously non-diseased parenchyma in FSGS
Glomerular sclerosis
with thick tubular
membranes and
advanced scar
Shrunken mature scars
and healthy interstitial
connective tissue
Manjeri A. Venkatachalam et al. JASN doi:10.1681/ASN.2015010006
Failed tubule differentiation after AKI lead to
hemodynamic abnormalities that cause progression.
Manjeri A. Venkatachalam et al. JASN doi:10.1681/ASN.2015
How AKI Contributes to CKD Progression
• AKI is self-healing, but if severe => tubular
atrophy, interstitial fibrosis, and long-term CKD
• If AKI is massive or superimposed on CKD,
injured tubules heal poorly and cause severe
scarring with loss of peritubular capillaries
=> salt-sensitive HTN
• HTN = ↑ damages glomeruli
Manjeri A. Venkatachalam et al. JASN doi:10.1681/ASN.2015010006
The importance of the
tubules in other models
J. Oliver and A. Luey published in 1935 about glomeruli
disconnected from tubules in patients with CKD
J. Oliver and A. B. Luey, Arch.Pathol. 19, 1-23 (1935).
Many clinical renal disorders lead to
the formation of atubular glomeruli
Children
– Obstructive nephropathy
– Pyelonephritis
– Congenital nephrotic syndrome
– Cystinosis
Adults
– IgA and membranous GN
– Diabetes (types I and II)
– Renal artery stenosis
– Transplant rejection
Chevalier & Forbes JASN 19:197-206, 2008
The Proximal Tubules account for
most of the nephron loss
•
Forbes MS et al. Am J. Physiol. Renal 303:F120-F129, 2012
Proximal Tubular Injury in the Obstructed Kidney
4-hydroxynonenal
(marker of
oxidative stress)
KIM-1
(marker of
proximal
tubular
injury)
M. S. Forbes, B. A. Thornhill, R. L. Chevalier, Am.J.Physiol. 301:F110-F117(2011).
Nephropathic Cystinosis
• Cystinosis, a disorder due to a mutation in cystinosin,
generally leads to renal failure by the second decade.
• The primary renal lesion, “swan neck” deformity of the
proximal tubule, develops between 6-12 months of age.
5 months
14 months
Mahoney & Striker. Pediatr Nephrol 2000
Fanconi syndrome
RENAL
FAILURE
<50% GFR
Oxidative stress
ATG
Proximal Tubular Mass
Swan Neck Progression
Maturation
Fibrosis
PT destruction
PT adaptation
Mouse
Birth
3m
6m
9m
12 m
Birth
6m
1y
2y
3y
24m
Man
4y
5y
Galarreta, Forbes, Thornhill, Antignac, Gubler, Nevo, Murphy, Chevalier. Am J Physiol 2015
18y
Fanconi syndrome
RENAL
FAILURE
<50% GFR
Oxidative stress
ATG
Proximal Tubular Mass
Swan Neck Progression
Maturation
Fibrosis
PT destruction
PT adaptation
Mouse
Birth
3m
6m
9m
12 m
Birth
6m
1y
2y
3y
24m
Man
4y
5y
Galarreta, Forbes, Thornhill, Antignac, Gubler, Nevo, Murphy, Chevalier. Am J Physiol 2015
18y
Returning to our patient…
A Call at the 11th hour…
• A 10 y.o. male with SCr 353.6 µmol/L (4 mg/dl),
has oliguria unresponsive to furosemide and has
CKD 3A (eGFR 50 mL/min/1.73 m2) due to PUV
• Response to aldosterone/ADH is impaired so by
the time oliguria occurs, there is a lot of injury…
• Questions to ask:
– How old is the patient?
– Co-morbidities?
Points to remember
• Patients with CKD/ESKD will
have more long-term damage
from an episode of AKI
• Residual renal function needs to
be protected!
• Call your friendly nephrologist
EARLY and OFTEN
Thank you.