Sickle Cell Nephropathy

Caroline Booth
Paediatric Nephrology
 Powars et al (1991)
• 25 yr observational study
• 725 patients most observed from birth or
early childhood
• 4% developed renal failure at a median age
of 23 yrs
• Survival once in renal failure 4yrs
• Study increased and extended by 15yrs –
12% patients developed ESRF by 37yrs
 Renal involvement
• More frequent in HbSS than HbSC
• Exception renal medullary carcinoma
• Develop nephron loss and compensatory
hypertrophy
• Prevalence of proteinuria increases with age,
estimated at 20-30%.
• Decreased renal function 5-25%
• Renal infarcts and papillary necrosis 30-40% in
radiological studies
 Pathologies
• Papillary necrosis
• Glomerular enlargement
• Focal segmental glomerulosclerosis
• Type 1 membranoproliferative
glomerulonephritis without immune
complex deposits
 Papillary necrosis
• Hypoxia, hypertonic, acidic
• Loss of Vasa Recta
• Symptoms –
– Gross painless haematuria15-40%
– Asymptomatic in up to 67%
• 10% bilateral, left 4x more than right
 Tubular defects

– Concentrating defect – irreversible by age

15yrs
– incomplete type IV renal tubular acidosis
– Impaired potassium secretion
– Hyponatraemia in crises
– Increased tubular reabsorption of phosphate &
b-microglobulin and increased secretion of uric
acid and creatinine
 Renal haemodynamics
• Increased glomerular filtration rate
• Increased renal plasma blood flow
• Biopsy increase in glomerular size - 87% larger
• May be mediated by increased production of
• prostaglandins,
• prostacyclin,
• nitirc acid
 FSGS
• Oxidative stress – ischemic reperfusion
injury with associated chronic inflammatory
response
• Hyperfiltration – very common lesion in
Sickle cell disease
• Proteinuria
• ?ongoing vascular endothelial damage
 Issues in Paediatrics
• High prevalance of proteinuria (P) in
children 19 -26% increasing with age
• Microalbuminuria (MA) 46% by teens
• Some papers have shown correlation with
degree of anaemia (Alvarez et al 2008)
• Others do not (Guasch et al 2008)
 Diabetes
• Strong association with hyperfiltration
microalbuminuria and renal impairment
• Long term studies strong association
between progression of microalbuminuria
and future development of renal impairment
• These studies are not available for HBSS
• Alvarez et al (2008) showed no progression
but retrospective and short term
 Monitoring
• Progression to renal impairment uncertain
• Need to monitor in all children
• Recommend annual urinary albumin
measurements
• Blood pressure review – should be low
hypertension poor prognostic indicator
• Renal function ?best way
 Early Markers
• Voskaridou et al 2006
• Studied cystatin C, NAG, b2-microglobulin,
creatinine clearance
• Cystatin C and serum b2- microglobulin
showed strong correlation with creatinine
clearance and age
• NAG positively correlated with proteinuria
 Intervention
• Optimise sickle cell management
• NSAIDS – isolated reports no long term
benefit
• Immunosuppressive drugs – as above
• Hydroxyurea – Shown to decrease
proteinuria short term
• ACE1 short term use reduce proteinuria but
with cessation worsening
 What we are doing
• Initially looking at a cross section of
patients
• The first groups were transfusion dependent
patients
• Performed GFRs and measuring true
creatinine, ADMA and SDMA,NAG, RBP
and looking for microalbuminuria
 Plasma creatinine v Inutest GFR

70

60
Plasma creatinine (µmol/l)

50

40

30

20

y = -0.1478x + 58.373
10 2
R = 0.1325

0
0 20 40 60 80 100 120 140 160 180 200
2
Inutest GFR (ml/min/1.73m )
 eGFR v Inutest GFR

250

200
eGFR (ml/min/1.73m2)

150

100

50 y = 0.7323x + 51.911
R2 = 0.2888

0
0 20 40 60 80 100 120 140 160 180 200

Inutest GFR (ml/min/1.73m 2)

 Figure 2. Plasma SDMA v GFR

6.00

5.00
SDMA (µmol/l)

4.00

-0.7998
3.00 y = 20.563x
2
R = 0.8888
2.00

1.00

0.00
0 20 40 60 80 100 120 140
GFR (ml/min/1.73m2)
 Plasma SDMA v Inutest GFR

0.7

0.6
Plasma SDMA (µmol/l)

0.5

0.4

0.3

0.2

0.1 y = -0.0029x + 0.7951

2
R = 0.4997
0
0 20 40 60 80 100 120 140 160 180 200
2
Inutest GFR (ml/min/1.73m )
 Future
• Big questions remain as

– When to start treatment

– What with
– How long for