Transcript New approaches to the management of the patient with SCD and CKD

autosomal recessive
genetic disease
substitution of valine for
glutamic acid at position 6
of the β-globin gene
Sickle cell disease (SCD) is the commonest
hemoglobinopathy in Jamaica with an
incidence of 1:150 live births
What I Hope to Achieve
SICKLE CELL NEPHROPATHY
Pathophysiology of Sickle nephropathy
Treatment of SCD with CKD
Summary
Sickle Cell Nephropathy (SCN)
A functional and structural abnormality.
It is most pronounced in homozygous HBSS (HbAS, HbSC, HbSD, HbSE,
and HbSthal [1].
far less frequent and severe in HbSC and HbAS than other phenotypes
[2,3]
1.
2.
3.
L. W. Status van Eps, Sickle cell disease. Atlas of kidney disease; 2004.
V. K. Derebail, P. H. Nachman, N. S. Key, H. Ansede, R. J. Falk, and A. V.
Kshirsagar, “High prevalence of sickle cell trait in African Americans with
ESRD,” JASN, 2010.
L. François, H. Nadjib, S. S. Katia, et al., “Hemoglobin SC disease
complications: a clinical study of 179 cases,” Haematologica, 2012.
PREVALENCE AND DETERMINANTS OF CKD IN SCD
primary cause of kidney disease
1% of the cases of renal dysfunction in the island (1)
Caribbean Renal Registry
40
35
30
25
20
15
10
5
0
Renal failure has contributed to about 18% of death in
Jamaican patients >40 with the HbSS disease (2)
major determinants of the prevalence of proteinuria are age
and genotype (3)
1. Barton WIMJ 2004
2. Thomas BMJ 1982
3. Powars Annals 1991
PATHOPHYSIOLOGY
normal renal medullar environment
which is characterised by low oxygen
tension, low pH, and high osmolality.
These conditions predispose to red
blood cell sickling, increased blood
viscosity leading to ischemia, and
eventual infarction of renal
microcirculation.
As glomerulosclerosis progresses GFR starts to decrease
and nonselective proteinuria leading to CKD/ESRD.
RBC sickling in the vasa rectae interferes with the
countercurrent exchange mechanism in the inner medulla.
The resulting impairment of free water resorption manifests
clinically as nocturia or polyuria
Glomerular
ischemia leads
to
compensatory
increase in
RBFand (GFR
PROTEINURIA
HYPERFILTRATION
RENAL FAILURE
HEMATURIA
GLOMERULOPATHY
PROTEINURIA
Prevalence of 25-59%
early sign and increases with age,
is a predictor of progression of SCN.
Clinical Diagnosis of sickle Nephropathy
Treatment of SCD with CKD
Summary
HEMATURIA
Gross hematuria can be secondary to papillary necrosis
resulting from medullary ischemia and infarction.
The sloughed papillae may obstruct urinary tract
outflow leading to obstructive nephropathy and
consequently renal failure
GLOMERULAR AND TUBULAR CHANGES
glomerular and tubular ischaemia
iron overload and subsequent deposition in the kidneys
intracapillary fragmentation and phagocytosis of sickled red
cells, immune complex formations,
FSGS associated with glomerular hyperfiltration, and/or
intrinsic glomerular capillary injury
P. T. T. Pham, P. C. T. Pham, A. H. Wilkinson, and S. Q. Lew, “Renal
abnormalities in sickle cell disease,” Kidney International, vol. 57, no. 1,
pp. 1–8, 2000
RENAL FAILURE
severe anaemia, hypertension, proteinuria, nephrotic
syndrome, and microscopic hematuria are significant
predictor of chronic renal failure
Clinical Diagnosis of sickle Nephropathy
0.11% of ESRD reported in the USRDS 93% of them were
African American
D. R. Powars, D.
D. Elliott-Mills,
L. Chan et al.,
“Chronic renal
failure in sickle
cell disease: risk
factors, clinical
course, and
mortality,”
Annals of
Internal
Medicine, vol.
115, no. 8, pp.
614–620, 1991.
HISTOLOGY OF SCN
Initially normal size or enlarged then shrunken
glomerular enlargement, haemosiderin deposit
chronic tubulointerstitial nephritis secondary
papillary necrosis, cortical infarction
to analgesic-abuse nephropathy
FSGS, membranoproliferative glomerulonephritis
tubular atrophy, and interstitial fibrosis
APPROACH TO MANAGEMENT
Veno-ooclussive crisis and chronic pain syndrome
Chronic hemolytic anaemia and Anaemia management
Prevention (Immunization) and treatment of infections
CKD progression and Renal Replacement Therapy
Novel therapies
NEWER APPROACHES
Hydroxyurea
Erythropoietin
Kidney transplantation
RAAS Blockage and Iron chelators
Allogeneic bone marrow transplantation (BMT) can cure SCD
A. O. Ojo, T. C. Govaerts, R. L. Schmouder et al.,
TRANSPLANT SURVIVAL
“Renal transplantation in end-stage sickle cell
AND COMPLICATIONS
nephropathy,” Transplantation, vol. 67, no. 2,
pp. 291–295, 1999.
Abbott et al. 2002Risk of mortality same as in
transplanted non sickle cell disease
Delayed function 24%
Acute rejection 26%
1-year graft survival 78%
3-year graft survival 46%
1-year patient survival 78%
3-year patient survival 59%
Median survival 33 months
Recurrent nephropathy
O'Rourke et al. 2008Recurrent allograft
dysfunction from vascular congestion and
tubular necrosis
Scheinman 2009
10-year patient survival 56%
Kim et al. 2011Intragraft sickle cell
vasoocclusive crisis as a cause of early allograft
loss
Augmentation by EPO of Fetal-Hb
response to hydroxyurea in SCD
Griffin 1993
Six Months of Hydroxyurea
Reduces Albuminuria in
Patients with Sickle Cell
Disease
JASN 2015
Enalapril and hydroxyurea
therapy for children with
sickle nephropathy
Courtney D. Fitzhugh
Pediatric Blood and Cancer
HYDROXYUREA
Effect of Hydroxyurea on Mortality and
Morbidity in Adult Sickle Cell Anemia
Risks and Benefits Up to 9 Years of Treatment
Martin H, JAMA 2003
Angiotensin Blockage with Losartan Is
Associated with Decreased Albuminuria and
Stable Renal Function in Adults and Children
with HbSS on Hydroxyurea
Marianne E. Yee, Peter A. Lane, James R. Eckman and
Antonio Guasch Blood 2015
Management pathway for renal complications in sickle cell disease.
…S0
IN SUMMARY
Claire C. Sharpe, and Swee Lay Thein Blood 2014;123:3720-3726
©2014 by American Society of Hematology