Renal Sickle Talk for Hbopathy Course

8/14/2019 Renal Sickle Talk for Hbopathy Course

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The Adult Kidney in Sickle

Cell Disease

Cormac Breen

Consultant NephrologistGuys and St Thomas Foundation Hospitals


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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


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Pathophysiology of kidney dysfunction

in SCD Clinical consequences of sickling in the

kidney





Established kidney disease

End stage kidney disease


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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 childrenover 2


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

molecular pathogenesis of sickle cell disease.

PathophysiologyPathophysiology

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

making sickle cell disease the first genetic disorder whose

molecular basis was known.

valine

HbS

glutamic acid Beta globin chain

lysine

HbC

The polymer has the form of an elongated rope-

like fibre.


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Vaso-occlusive events and haemolysis are theVaso-occlusive events and haemolysis are the

clinical hallmarks of sickle cell diseaseclinical 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


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Vasa rectaVasa recta

normal kidneynormal kidney sickle cellsickle cell

traittrait

sickle cellsickle cell

diseasedisease

Strauss and Welt's Diseases of the Kidney,

(3rd ed)


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Pathophysiology of kidney dysfunction in

SCD

Clinical consequences of sickling in the

kidney








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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 450mosmol/kg

Nocturia manageable only by behavioural adjustment


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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.


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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


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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 normalplasma bicarbonate).

Abnormal proximal tubule function:

Supranormal function leading to hyperphosphataemia andincreased creatinine secretion.


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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


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ThompsonThompson et alet alArch Intern Med. 2007 Apr 9;167(7):701-8

65 patients with SCD (recruited from birth)

Followed up between ages 18 and 23compared 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)


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Papillary necrosis

haematuria

? Medullary carcinoma

Loss of vasa recta

Loss of urinary

concentratingability

Polyuria and

nocturia

dehydration

Renal failure

Medullary ischaemia

Prostaglandins+

Nitric oxide

Renal blood flowand GFR

hyperfiltration

Glomerular hypertrophyand proteinuria


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SCD


kidney







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PlattPlatt et alet al, 1994, 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

PowarsPowars et alet al, 1991, 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

ModellModell et alet al, 2007, 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.


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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 AS


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SCD


kidney


Routine out-patient supervision Management of specific problems




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Routine clinic checks

At every visit Bp

Urine dipstix

Every 6 months Hb

Albumin-creatinine ratio (ACR)

Creatinine eGFR


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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


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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 least2 occasions)

Investigation

serology Renal ultrasound

Recommend treatment ACEi or ARB

If proteinuria persists consider 2nd agent


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ThompsonThompson et alet 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


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SCD


kidney



Management of specific problems Prior to established kidney disease



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Avoid / treat hypertension and proteinuria

Avoid nephrotoxic medication (NSAIDs) Adequate hydration

Investigate new onset proteinuria and haematuria


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SCD


kidney



Management of specific problems Prior to established kidney disease



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Control blood pressure tightly

Treat proteinuria

Manage in liaison with nephrologist (joint clinic) Slow / arrest progression of functional kidney loss


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Erythropoietin therapy

LittleLittle et alet al, Haematologica 2006, Haematologica 2006

Review of the literature and the National Institutes of health experiencerecommend:

Consider useConsider use in patients with end-organ damage ANDAND Hb 1.5 g/dl over 4weeks

Monitor FBC and BP weekly after dose change.


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SCD


kidney


Routine out-patient supervision Management of specific problems





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DialysisDialysis


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Saxena et al, Transplantation 2004Saxena 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 1Group 1 Group 2Group 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%


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3.223.22( 0.2)

Range 0.25-9.4

n=89

10.7610.76( 0.97)

Range 2-19.6

n=24

6060

( 1.18)

Range 25-82

n=113

1.991.99

( 0.22)

Range 0-12

n=83

50.550.5

(0.94)

Range 16-69

n=259

Non-SCD

Black African/

Caribbean

Control group

(under 70)

2.92.9( 1.25)

n=3

9.679.67( 0.33)

n=3

38.638.6( 2.1)

n=5

* * p


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Breen and Macdougall, 1998

Improvement in erythropoietin-resistant anaemia after renalImprovement in erythropoietin-resistant anaemia after renal

transplantation in patients with homozygous sickle-cell diseasetransplantation in patients with homozygous sickle-cell disease

at KCHat KCH

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

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HD Tx

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HDTx HD

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Epo 12,000-30,000 units/wk

Tx

Epo 20,000 units/wk

Epo 12,000 - 30,000 units/wk

HD

Sharpe, personal communication 2008


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TransplantationTransplantation


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Renal transplantationOutcome 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


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Renal transplantationAbbott et al, 2002 Clin NephrolAbbott et al, 2002 Clin Nephrol

Retrospective analysis of patients receiving RRT from theUnited 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 mortalitywith 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


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3.223.22( 0.2)

Range 0.25-9.4

n=89

10.7610.76( 0.97)

Range 2-19.6

n=24

6060( 1.18)

Range 25-82

n=113

1.991.99( 0.22)

Range 0-12

n=83

50.550.5(0.94)

Range 16-69

n=259

Non-SCD

Black African/

Caribbean

Control group

(under 70)

2.92.9( 1.25)

n=3

9.679.67( 0.33)

n=3

38.638.6( 2.1)

n=5

* * p


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Breen and Macdougall, 1998

Improvement in erythropoietin-resistant anaemia after renalImprovement in erythropoietin resistant anaemia after renal

transplantation in patients with homozygous sickle-cell diseasetransplantation in patients with homozygous sickle-cell disease

at KCHat KCH

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

0

2

4

6

8

10

12

20/5/04

20/7/04

20/9/04

20/11/04

20/1/05

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HD Tx

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HDTx HD

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1/07

26/2/08

Epo 12,000-30,000 units/wk

Tx

Epo 20,000 units/wk

Epo 12,000 - 30,000 units/wk

HD

Sharpe, personal communication 2008


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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


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ConclusionConclusion

Sickle cell nephropathy is a relatively common and significant complication of sickle cell

disease, though most patients dont progress to end-stage renal failure

Advanced kidney disease is associated with a markedly decreased life expectancy

Epo therapy may be useful when eGFR

Documents

Renal Sickle Talk for Hbopathy Course