The Adult Kidney in Sickle

Cell Disease
Cormac Breen
Consultant Nephrologist
Guy’s and St Thomas’ Foundation Hospitals
 Overview
• Pathophysiology of kidney dysfunction in SCD
• Clinical consequences of sickling in the kidney
• The scale of the problem
• Routine out-patient supervision
• Management of specific problems
– Prior to established kidney disease
– Established kidney disease
– End stage kidney disease
• Pathophysiology of kidney dysfunction
in SCD
• Clinical consequences of sickling in the
kidney
• The scale of the problem
• Routine out-patient supervision
• Management of specific problems
– Prior to established kidney disease
– Established kidney disease
– End stage kidney disease
 History of sickle nephropathy
• Peculiar elongated and sickle-shaped red blood corpuscles in a case of
severe anemia. James B Herrick; Archives of Internal Medicine 6:517-520, 1910

“Increased urine volume of low specific gravity”

• Sydenstricker, Mulherin and Houseal, 1923

“prominent glomeruli distended with blood”

• Bernstein and Whitten, 1960 and Buckalew and Someren, 1974

Glomerular enlargement and congestion were more frequent in children

over 2
 Pathophysiology

In 1956, Vernon Ingram and J.A. Hunt sequenced sickle hemoglobin

making sickle cell disease the first genetic disorder whose
molecular basis was known.
glutamic acid Beta globin chain

valine lysine
HbS HbC

The polymerization of deoxy Hb S is the primary event in the

molecular pathogenesis of sickle cell disease.

The polymer has the form of an elongated rope-

like fibre.
 Vaso-occlusive events and haemolysis are the
clinical hallmarks of sickle cell disease

Polymerization alone does not account for the pathophysiology of

sickle cell disease.

Other factors include:

• changes in red cell membrane structure and function

• disordered red cell volume control

• increased red cell adherence to vascular endothelium

• abnormal regulation of vasoactivity

 Vasa recta

normal kidney sickle cell sickle cell

trait disease

Strauss and Welt's Diseases of the Kidney,

(3rd ed)
• Pathophysiology of kidney dysfunction in
SCD
• Clinical consequences of sickling in the
kidney
• The scale of the problem
• Routine out-patient supervision
• Management of specific problems
– Prior to established kidney disease
– Established kidney disease
– End stage kidney disease
Impaired urinary concentration
• leads to nocturia and polyuria

• initially reversible by blood transfusion often

irreversible by age 10

• maximum urine osmolality in adults is 400 to 450

mosmol/kg

• Nocturia manageable only by behavioural adjustment

 Haematuria
• Painless microscopic or gross haematuria is
common,
• usually mild, unilateral and self limiting,
• usually caused by papillary infarcts.

• Papillary necrosis may cause painful gross

haematuria and occasionally urinary obstruction.

• Haematuria may rarely be caused by renal medullary

carcinoma.
 Proteinuria
• GFR tends to fall by the end of the 2nd decade
• usually reduced by age 30, though few progress to
ESRF.
• Often associated with slowly progressive proteinuria.
• Renal biopsy typically shows glomerular enlargement
and FSGS.
• nephrotic syndrome (prot > 3g) may be due to
membranoproliferative GN, FSGS or SCN
• Renal vein thrombosis is a recognised complication
 Abnormal tubular function
• Abnormal distal and collecting tubule function:

Impairment of distal hydrogen ion and potassium ion secretion

leading to high urine pH and hyperkalaemia (but usually normal
plasma bicarbonate).

• Abnormal proximal tubule function:

Supranormal function leading to hyperphosphataemia and

increased creatinine secretion.
 Changes in BP and GFR
Increased GFR:
• Predominantly young patients.
• Prostaglandin + nitric oxide-mediated in response to medullary
ischaemia.
• Also associated with increased cardiac output.
• Potentially prodrome for kidney disease

Hypertension
• Incidence of hypertension low compared to general population
• Hypotension common, due in part to salt & water wasting
• Modest levels of hypertension may be more significant; greater
sensitivity to BP
Thompson et al
Arch Intern Med. 2007 Apr 9;167(7):701-8

65 patients with SCD (recruited from birth)

Followed up between ages 18 and 23
compared to 15 normal controls controls

Median isotopic GFR: Men 137 (range 21-210)

women 126 (range 77-263)

Creatinine clearance measurements were consistently higher than isotopic GFR in patients
with HBSS disease

Creatinine clearance: Men 144 (range 32-419)

women 145 (range 71-262)
 Loss of vasa recta

Papillary necrosis Medullary ischaemia
Loss of urinary 
concentrating 
ability
Prostaglandins
+
Nitric oxide
Polyuria and 
haematuria nocturia

Renal blood flow 
and GFR dehydration

hyperfiltration

? Medullary carcinoma
Glomerular hypertrophy 
and proteinuria Renal failure
• Pathophysiology of kidney dysfunction in
SCD
• Clinical consequences of sickling in the
kidney
• The scale of the problem
• Routine out-patient supervision
• Management of specific problems
– Prior to established kidney disease
– Established kidney disease
– End stage kidney disease
Platt et al, 1994
N Engl J Med.

Prospective survival analysis of 3764 patients with SCD across 23 centres in the US
over 10 years.

• 209 deaths
• HBSS disease, median age at death: 42 years for men
48 years for women

• 10.5% of the deaths were associated with renal impairment

Powars et al, 1991

Ann Intern Med.

• 4.2% patients with HBSS disease developed end-stage renal failure (CKD 5)
• Median age of disease onset was 23.1 years, mean age of death 27

Modell et al, 2007

Scand J Clin Lab Invest.

Over 300,000 people in the UK carry the haemoglobin S gene and over 12,000
suffer from sickle cell disease, the majority of whom live in London.
 Local data

• 80 patients in clinic over age 40

• 43% with HbSS & 42% HbSC have kidney disease
• Most have proteinuria
• BP control in 50%
• Tendency towards having other microvascular
disease

Thomson et al, 2008, submitted to ASH

• Pathophysiology of kidney dysfunction in
SCD
• Clinical consequences of sickling in the
kidney
• The scale of the problem
• Routine out-patient supervision
• Management of specific problems
– Prior to established kidney disease
– Established kidney disease
– End stage kidney disease
 Routine clinic checks
• At every visit
• Bp
• Urine dipstix

• Every 6 months
• Hb
• Albumin-creatinine ratio (ACR)
• Creatinine
• eGFR
 Management for abnormal findings
Hypertension

If no proteinuria
• treat if Bp >140/90.
• Aim for target of 130/80

If proteinuria present
• treat if Bp > 130/80
• Aim for target of 120/80
• Use anti-proteinuric therapy
 Management for abnormal findings
Proteinuria
• Dipstix negative and ACR 5-50
• Repeat 6 monthly
• Dipstix proteinuria
• Send for Protein-Creatinine ratio (PCR) and MSU
• Dipstick positive & ACR >50 or PCR >50 (on at least
2 occasions)
• Investigation
• serology
• Renal ultrasound
• Recommend treatment
• ACEi or ARB
• If proteinuria persists consider 2nd agent
Thompson et al
Arch Intern Med. 2007 Apr 9;167(7):701-8

65 patients with SCD (recruited from birth)

Followed up between ages 18 and 23
compared to 15 normal controls controls

26% patients with SS disease had albuminuria compared to none of the

controls

The presence of albuminuria correlated positively with GFR (154 vs 126

(p=0.02)) and systolic BP (110/61 vs 102/58 (p<0.05))
• Pathophysiology of kidney dysfunction in
SCD
• Clinical consequences of sickling in the
kidney
• The scale of the problem
• Routine out-patient supervision
• Management of specific problems
– Prior to established kidney disease
– Established kidney disease
– End stage kidney disease
 Prior to established kidney disease

• Avoid / treat hypertension and proteinuria

• Avoid nephrotoxic medication (NSAID’s)
• Adequate hydration
• Investigate new onset proteinuria and haematuria
• Pathophysiology of kidney dysfunction in
SCD
• Clinical consequences of sickling in the
kidney
• The scale of the problem
• Routine out-patient supervision
• Management of specific problems
– Prior to established kidney disease
– Established kidney disease
– End stage kidney disease
 Established kidney disease

• Control blood pressure tightly

• Treat proteinuria
• Manage in liaison with nephrologist (joint clinic)
• Slow / arrest progression of functional kidney loss
 Erythropoietin therapy
Little et al, Haematologica 2006

Review of the literature and the National Institutes of health experience

recommend:

Consider use in patients with end-organ damage AND Hb<8 g/dl AND GFR
<100 AND when hydroxyurea dose is limited by reticulocyte count<
100,000/µl

Dose: s/c 100u/kg twice a week increasing by 100U/kg/dose every 4-6

weeks until Hb rises. Stop if Hb > 10.5 g/dl or if rise is > 1.5 g/dl over 4
weeks

Monitor FBC and BP weekly after dose change.

• Pathophysiology of kidney dysfunction in
SCD
• Clinical consequences of sickling in the
kidney
• The scale of the problem
• Routine out-patient supervision
• Management of specific problems
– Prior to established kidney disease
– Established kidney disease
– End stage kidney disease
Dialysis
Saxena et al, Transplantation 2004
compared 11 (group1) patients with ESRD due to SCN with
192 patients with other cause ESRD (group 2) on haemodialysis
between 1992 and 1999 in Saudi Arabia.

Group 1 Group 2

Mortality 11.59% 5.87%

Age at death 31 47.8

Time on HD 27 months 44.2 months

Septicaemic episodes 2.59/100 p.m. 1.19/100 p.m.

No. blood transfusions 13.7 units 8.2 units

HBV infecion 18.2 % 4.64%

HCV 63.6% 44.3%

Patients with Average age Average wait for Average age Average time Average time
CKD stage 5 on starting first transplant on death from ESRD to from ESRD to
dialysis (years) death: death:
Transplanted Non-
(years) transplanted
(years)

SCD 31 3.02 38.6 9.67 2.9

(± 2.74) (± 1.17) (± 2.1) (± 0.33) (± 1.25)
Range 20-49 Range 0.2-8.7 n=5 n=3 n=3
n=11 n=7 * * p<0.01
* *p<0.01 * p<0.05

Non-SCD 50.5 1.99 60 10.76 3.22

Black African/ (±0.94) (± 0.22) (± 1.18) (± 0.97) (± 0.2)
Range 16-69 Range 0-12 Range 25-82 Range 2-19.6 Range 0.25-9.4
Caribbean n=259 n=83 n=113 n=24 n=89
Control group
(34)
(34 (39) (12.7) (2.8)
(under 70)
n=6 n=16
 Breen and Macdougall, 1998

Nephrol Dial Transplant. 1998 Nov;13(11):2949-52

0
2
4
6
8
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26/2/05
0
2
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6
8
10
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HD
20/5/04
0
2
4
6
8
10
12

23/6/97
20/7/04
26/5/05
at KCH

20/9/04 23/2/98

20/11/04
26/8/05 23/10/98
HDTx

20/1/05

20/3/05 23/6/99
26/11/05

20/5/05
23/2/00

26/2/06 20/7/05
23/10/00
20/9/05
HD

26/5/06 20/11/05 23/6/01

20/1/06
23/2/02

Epo 12,000-30,000 units/wk

26/8/06 20/3/06

20/5/06 23/10/02

26/11/06 20/7/06
23/6/03
Epo 20,000 units/wk

20/9/06
Tx

Tx

26/2/07 23/2/04
20/11/06

20/1/07
23/10/04
26/5/07
20/3/07
Epo 12,000 - 30,000 units/wk

23/6/05
20/5/07
26/8/07
20/7/07 23/2/06
HD

20/9/07
26/11/07 23/10/06
20/11/07

20/1/08 23/6/07
26/2/08
20/3/08
23/2/08

20/5/08
Improvement in erythropoietin-resistant anaemia after renal
transplantation in patients with homozygous sickle-cell disease

Sharpe, personal communication 2008

Transplantation
 Renal transplantation
Outcome studies show acceptable survival for living and
cadaveric grafts
• 82 age-matched AA SCN pts compared to 22,565 controls
(ESRD all causes)
• 1 year graft survival 77% SCN vs. 78%
• Graft loss RR adjusted 1.39 (ns)
• 3 year graft survival 48% v. 60% (p = 0.055)
• Adjusted RR 1.60 (p = 0.003)
Results less good than other causes ESRD (UNOS)

Ojo et al, Transplantation 1999

 Renal transplantation
Abbott et al, 2002 Clin Nephrol

• Retrospective analysis of patients receiving RRT from the

United States Renal data System from 1992 to 1997
• 375,152 patients
• 397 (0.11%) had SCN, of whom 93% were African-Americans
• Mean age at presentation to ESRD was 40.68 +/- 14 years
• SCN patients had an independently increased risk of mortality
with a hazard ratio of 1.52

• Post transplantation, the presence of SCN was no longer an

independent risk factor

• However, sickle cell patients were much less likely to be placed

on the transplant waiting list or to receive a renal transplant
• Probably represents a better option than dialysis
Patients with Average age Average wait for Average age Average time Average time
CKD stage 5 on starting first transplant on death from ESRD to from ESRD to
dialysis (years) death: death:
Transplanted Non-
(years) transplanted
(years)

SCD 31 3.02 38.6 9.67 2.9

(± 2.74) (± 1.17) (± 2.1) (± 0.33) (± 1.25)
Range 20-49 Range 0.2-8.7 n=5 n=3 n=3
n=11 n=7 * * p<0.01
* *p<0.01 * p<0.05

Non-SCD 50.5 1.99 60 10.76 3.22

Black African/ (±0.94) (± 0.22) (± 1.18) (± 0.97) (± 0.2)
Range 16-69 Range 0-12 Range 25-82 Range 2-19.6 Range 0.25-9.4
Caribbean n=259 n=83 n=113 n=24 n=89
Control group
(34)
(34 (39) (12.7) (2.8)
(under 70)
n=6 n=16
 Breen and Macdougall, 1998

Nephrol Dial Transplant. 1998 Nov;13(11):2949-52

0
2
4
6
8
10
12
26/2/05
0
2
4
6
8
10
12

HD
20/5/04
0
2
4
6
8
10
12

23/6/97
20/7/04
26/5/05
at KCH

20/9/04 23/2/98

20/11/04
26/8/05 23/10/98
HDTx

20/1/05

20/3/05 23/6/99
26/11/05

20/5/05
23/2/00

26/2/06 20/7/05
23/10/00
20/9/05
HD

26/5/06 20/11/05 23/6/01

20/1/06
23/2/02

Epo 12,000-30,000 units/wk

26/8/06 20/3/06

20/5/06 23/10/02

26/11/06 20/7/06
23/6/03
Epo 20,000 units/wk

20/9/06
Tx

Tx

26/2/07 23/2/04
20/11/06

20/1/07
23/10/04
26/5/07
20/3/07
Epo 12,000 - 30,000 units/wk

23/6/05
20/5/07
26/8/07
20/7/07 23/2/06
HD

20/9/07
26/11/07 23/10/06
20/11/07

20/1/08 23/6/07
26/2/08
20/3/08
23/2/08

20/5/08
Improvement in erythropoietin-resistant anaemia after renal
transplantation in patients with homozygous sickle-cell disease

Sharpe, personal communication 2008

 Renal transplantation
• More studies than dialysis
• Most reports focus on survival data rather than
haematological response
• Provides possibility of normal erythropoietin
production
Potential barriers to successful Tx -immunological
- cardiac
- iron overload
- live donors
 Conclusion

• Sickle cell nephropathy is a relatively common and significant complication of sickle cell
disease, though most patients don’t progress to end-stage renal failure

•Advanced kidney disease is associated with a markedly decreased life expectancy

• Patients should be monitored for proteinuria and declining renal function and treated with
ACEI / ARB if significant proteinuria

• Epo therapy may be useful when eGFR <60 ml/min, reducing transfusion needs and
increasing HbF, though large doses will be required for any benefit

• Transplantation is the preferred treatment in patients with severe renal impairment