Sickle cell disease is a disorder that affect all systems including urinary systems, biochemical investigations may be used to identify early events and institute measures that will prevent progression to ESRD

1. By
Dr Auwal Ahmad
Department of Haematology
Moderated by
Dr J. M. El Bashir
1/29/2024
Biochemical Investigation and
Management of Sickle Cell
Nephropathy
1

2. Outline
 Introduction
 Epidemiology
 Pathophysiology
 Clinical features
 Investigations
 Management
 Conclusion
 References
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3. Introduction
 Sickle cell disorder is an autosomal recessive
disorder caused by a point mutation leading to
replacement of glutamic acid for valine at the
sixth amino acid of beta-globin
 In this disorder, RBCs become sickled when
exposed to conditions of low oxygen tension
 Polymerization of deoxygenated haemoglobin
 Red cell distortion, haemolytic anaemia, micro-
vascular obstruction, and ischaemic tissue
damage
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4. Introduction
 In Sickle cell disease (SCD), there is inheritance
of HbS
• Homozygous state (HbSS) referred to as Sickle cell
anaemia
• Heterozygous state
 Normal: eg HbA (HbAS) is the sickle cell trait
 Compound: HbC, HbD and HbE refered to as SCD
 The hallmark of SCD is haemolysis, widespread
vaso-occlusion, ischaemia reperfusion injury and
subsequent multi-organ damage
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5. Introduction
 Sickle cell disorders may lead to a variety of
alterations in renal morphology and function leading
to clinically significant abnormalities collectively
known as Sickle cell nephropathy. These are:
• Proteinuria
• Hyposthenuria
• Renal Papillary necrosis and Haematuria
• Sickle cell glomerulopathy
• Renal Tubular Disorders
 Significant renal involvement occurs more frequently
in SCD than in sickle cell trait
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6. Epidemiology
 SCD is prevalent in malaria-endemic regions due
to protective carrier state
 Increasing occurrence in non-endemic regions
due to population movements
 About 24% in adult Nigerians and about 8% in
African-Americans ----WHO 59th WHA
 Renal complications as significant cause of
morbidity and mortality
 Incidence of renal failure rising with improved
patient survival -------Aeddula NR et al island
2022
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7. Epidemiology
 Renal involvement occurs in ~60% of patients
with SCD only 4-12% will develop end-stage renal
disease (ESRD) (Powers et al 2005)
 SCN accounts for <1% of all new cases of ESRD
( US)
 Proteinuria is common in SCD occurring in about
30% of patients
 16-18% of mortality in SCD is ascribed to kidney
disease
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8. Epidemiology
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S/N Location Prevalenc
e
comment Reference
1 Zaria 66.3%
1.4%
2.5%
CKD in Addult
CKD4
microalbimunuria
R. Yusuf et al 2017
2 Maiduguri 38.9%
26..8%
3.5%
CKD
Hyperfiltration
ESRD
A.A., Bukar et al
2019
3 Oweri 3.4%
6.7%
Proteinuria
Haematuria
U. Nnagi et al 2020
4 Nigeria 26%
32.8%
Microalbimunuria
Increased eGFR
I. Ocheke et al
2019

9. Epidemiology---Risk Factors
 risk factors associated with progression of
chronic kidney disease (CKD) in SCN
 Genetic variants of MYH9 and APOL1
 Infection with parvovirus B19
 Recurrent Acute chest syndrome
 Vaso occlusive episodes
 Nephrotic range proteinuria
 Underlying hypertension
 Severe anemia
 Genetic modifiers may affect renal dysfunction
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10. Risk Factors
 Genetic Modifiers and Renal Dysfunction
 Renal dysfunction more severe in HbSS and
HbSb0 thalassaemia genotypes (SCA)
 Lower HbF levels correlate with renal failure risk
and vaso-occlusive complications
 Co-inheritance of α-thalassaemia reduces HbS
concentration, red cell volume, and haemolysis
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11. Pathophysiology
 Normal Kidney Physiology and SCN
 Kidneys filter plasma at ~100 ml/min/1.73 m² rate,
receive 25% cardiac output
 SCD phenotype variation but similar blood flow to
kidneys
 Renovascular pathology targeted by multi-organ
vasculopathy linked to chronic nitric oxide (NO)
depletion from intravascular haemolysis
 Activation of hypoxia inducible factor 1a (HIF1a) and
local Endothelin-1 release contribute to chronic
medullary hypoxia
 NO deficiency pivotal in pulmonary hypertension and
progression of SCN 1/29/2024
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12. Pathophysiology
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13. Pathophysiology
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14. Renal manifestations of sickle cell
disease
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 Alterations in renal haemodynamics
 Increased renal blood flow rate
 Increased renal plasma flow rate
 Increased glomerular filtration rate
 Decreased renal vascular resistance
 Decreased filtration fraction
 Decreased medullary perfusion
 Renal and glomerular enlargement
 Hyperfunction of the proximal tubule
 Increased reabsorption of phosphate and β2-
microglobulin
 Increased secretion of creatinine and uric acid

15. Renal manifestations of sickle cell
disease
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 Glomerulopathies
 Focal segmental glomerulosclerosis
 Membranoproliferative glomerulonephritis
 Thrombotic microangiopathy
 Tubular deposits of iron
 Chronic tubulointerstitial disease
 Impaired function of the distal nephron
 Decreased urinary concentrating ability
 Partial distal renal tubular acidosis
 Impaired renal potassium excretion

16. Renal manifestations of sickle cell
disease
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 Increased susceptibility to acute kidney injury
 Chronic kidney disease and its progression to end-
stage renal disease
 Haematuria
 Renal papillary necrosis
 Increased susceptibility to urinary tract infections
 Renal medullary carcinoma

17. Pathophysiology
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18. Clinical Features
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 Asymptomatic
 Diminished concentrating ability (hyposthenuria)
 Present with thirst, nocturia and polyuria
 Dehydration leading to acute vaso-occlusive crises
 Sickling in the vasa rectae interferes with countercurrent
exchange in the inner medulla
 Hematuria – Painless microscopic or gross hematuria
– Due to papillary infarcts, microthrombosis in
peritubular capillaries, infections, or transfusion
reaction
 Renal infarction & papillary necrosis
 Nausea, vomiting, flank or abdominal pain, fever
 Hypertension (renin-mediated) Renal tubular acidosis –
Diminished medullary blood flow and hypoxia ->
Impaired distal H and K secretion -> incomplete dRTA

19. Clinical Features
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 Abnormal proximal tubular function (Supranormal) –
Hyperphosphatemia <- increased phosphate
reabsorption – Elevated creatinine clearance (due to
enhanced creatinine secretion) in relation to the true
glomerular filtration rate (GFR)
 Acute kidney injury
 Impaired concentrating ability -> dehydration -> prerenal
AKI
 Intrinsic renal causes of AKI include rhabdomyolysis,
sepsis, drug nephrotoxicity, renal vein thrombosis, and
hepatorenal syndrome (hemosiderosis-induced hepatic
failure)
 Postrenal causes include urinary tract obstruction e.g.
secondary to blood clots

20. Clinical Features
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 Urinary tract infection – Impaired immunity
(autosplenectomy) -> opsonic antibody deficiency
- > encapsulated organisms)
 Can precipitate a sickle cell crisis
 Nephrotic Syndrome
 Rare -> poor prognosis
 MPGN -> FSGS – Direct effect of sickled RBCs
 Secondary MPGN <- hepatitis C infection (multiple
blood transfusions)

21. Clinical Features
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 CKD
 Symptoms develop slowly and aren't specific to the disease
 Asymptomatic, nausea and vomiting, fatigue, loss of appetite,
malaise, muscle cramps, swellings, dry and itchy skin,
breathlessness, insomnia, polyuria or oliguria,
 high blood pressure
 Renal medullary carcinoma
 Rare; ~ 1 in 20,000 • Almost exclusive with sickle cell trait
(less commonly, sickle cell disease)
 Present with gross hematuria, UTI, flank pain, an abdominal
mass, and/or weight loss
 Diagnosis via imaging (CT scan)
 Highly aggressive malignancy
 Metastasis at time of diagnosis
 Poor prognosis

22. Investigations
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 Biochemical and non biochemical
 Biochemical
 Urinalysis with microscopy using spot urine, morning
urine or 24hr urine collection
 Assess proteinuria/albuminuria
 Renal function panel
 Electrolytes, urea and critinine
 eGFR calculation using
 Inulin eGFR
 Creatinine eGFR
 Lipid profile
 Other markers of renal function

23. Investigations --- urinalysis
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 Physical examination describes the volume, color,
clarity, odor, and specific gravity.
 Chemical examination identifies pH, red blood
cells, white blood cells, proteins, glucose,
urobilinogen, bilirubin, ketone bodies, leukocyte
esterase, and nitrites.
 Microscopic examination encompasses the
detection of casts, cells, crystals, and
microorganisms.
 Proteinuria, haematuria, USG, PH

24. Investigations --- urinalysis
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 Proteinuria can my categorized as a glomerular
pattern, a tubular pattern, and an overflow pattern
 Albuminuria
 According to the Kidney Disease Improving
Global Outcomes (KDIGO) guidelines,
albuminuria can be classified into three stages
 uACR/uPCR

25. Investigations --- urinalysis
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Albuminuria
stage
Description ACR (mg/mmol
creatinine)
A1 Normal to mildly
increased
<3 Reference
ranges: women
<3.5 mg/mmol;
men <2.5
mg/mmol
A2 Moderately
increased
3-30 Commonly
referred to as
‘’micro-
albuminuria’’
A3
Example ;
G3bA2 denotes
GFR 30-
44mL/min & ACR
Severely
increased
>30 Detectable using
conventional
dipsticks

26. Investigations --- urinalysis
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 Haematuria
Dipstick test for blood detects primarily the
peroxidase activity of erythrocytes, but
myoglobin and hemoglobin can also catalyze
this reaction. Thus, a positive test result
indicates hematuria, myoglobinuria, or
hemoglobinuria.

27. Electrolytes, urea and critinine
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 INCREASED
 Potassium
 Urea
 Creatinine
 Hydrogen ion
 Phosphate
 Magnesium
 DECREASED
 Sodium
 Bicarbonate
 Calcium

28. eGFR
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CKD Stage GFR (mL/min/1.73m2) Description
1 >90 Normal or increased
GFR with other
evidence of kidney
damage
2 60-89 Mild reduction in GFR,
with other evidence of
kidney damage
3 30-59
3a 45-59
3b 30-44
Moderately reduced
GFR, with or without
evidence of kidney
injury
4 15-29 Severely reduced GFR
5 <15 End-stage or
approaching end-stage
kidney failure
5D <15 On dialysis

30. Investigations
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 Can be classified base on the renal structure affected by
the pathological process
 Markers of glomerular damage
 Transferrin
 igG
 Ceruloplasmin
 Type IV collagen
 Laminin
 Glycosaminoglycans
 Lipocalin type prostaglandin D synthase
 Fibronectin
 Podocalyxin
 VEGF
 Cystatin C
 nephrin

31. Investigations
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 Tubular damage markers
 Neutrophils gelatinase associated lipocalin(NGAL)
 Alpha-1-microglobulin
 Kidney injury molecule-1(KIM-1)
 N-acetyl-beta-D-glucosaminidase
 Angiotensinogen
 Uromodulin
 Liver type fatty-acid binding protein (L-FABP)
 Heart-type fatty acid binding protein (H-FABP)

32. Investigations
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 Non biochemical
 Hb electrophoresis
 Full blood count and Differential
 Viral serologies
 Renal ultrasound – Early - > large, variable
echogenicity – Shrink with CKD – Papillary necrosis
• Increased echogenicity of the inner medulla • In
more advanced cases, a filling defect in the area of
the medullary tip can be seen

33. Management
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 This can be divided into management of SCD and the
management of nephropathy
 SCD complications such as frequent crisis and
anaemia are controlled by;
- Blood transfusion
- Hydroxyurea (HU)
 HU may reduce proteinuria and hyperfiltration, better
urine concentrating ability and less renal enlargement

34. Management
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 Patients with proteinuria (uACR>50mg/mmol)
should be treated
 Either with an angiotensin converting enzyme
inhibitor (ACEI) or an angiotensin receptor
blocker (ARB) starting at a low dose
 When taken at night these drugs also reduce
nocturia
 Treatment of anaemia; the target Hb level should
be no greater than 10-10.5g/dL
 A rise in haematocrit of greater than 1-2% per
week should be avoided

35. Management
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 Erthrocyte-stimulating agents (ESA) such as
erythropoietin can improve Hb level and
reduce transfusion requirement in some
patients
 Though blood transfusion provides higher
amount of HbA compared with patients own
blood
 Addition of ESA may allow administration of
higher doses of HU and improve foetal Hb

36. Management
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 Haematuria in SCN is typically self-limiting
 Treatment consists of bed rest and
maintenance of high urine flow rate
 In cases of massive haematuria include;
 Urine alkalinization to minimize Hb
precipitation, loop diuretics to prevent micro-
tubular obstruction and blood transfusion to
reduce HbS and sickling

37. Management
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 Refractory cases may require high doses of
oral urea which has an inhibitory effect on
gelation of deoxygenated sickled Hb
 Treatment with vasopressin or epsilon amino
caproic acid to promote clotting
 Angiographic embolization of renal vessels or
balloon tamponade may be considered

38. Management
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 The relatively small size of the SCD-ESRD
population has limited the development of
optimal management strategies
 Renal replacement therapy is considered in
ESRD
 The therapeutic options include;
1. Haemodialysis
2. peritoneal dialysis
3. Kidney transplantation

39. Conclusion
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SCD
may lead to a variety of alterations in renal
morphology and function, some of which
produce clinically significant abnormalities that
may be present from the first year of life. The
lack of diagnostic test capable of detecting
those at risk, and detecting onset of
symptoms remains a barrier to instituting
therapy. The absence of therapeutic strategy
compounds the management of SCN

40. 1/29/2024
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 Thank you all for listening

41. References
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 Aeddula NR, Bardhan M, Baradhi KM. Sickle Cell Nephropathy. Ncbi.
2020. Available from https://www.ncbi.nlm.nih.gov . [Date accessed July,
2020]
 Alpers CE, Chang A. The Kidney. Robbins and Cotran Pathologic Basis
of Diseases. Saunders Elsevier. Ninth Edition. Chapter 20. Pg 911-919
 Inusa BPD, Mariachiara L, Giovanni P, Ataga KI. Sickle Cell
Nephropathy: Current Understanding of the Presentation, Diagnostic
and Therapeutic Challenges. Intechopen. 2018. Available from
https://www.intechopen.com .[Date accessed July, 2020]
 Kumar V, Abbas AK, Aster JC. Red Blood Cell and Bleeding Disorders.
Robbins and Cotran Pathologic Basis of Diseases. Saunders Elsevier.
Ninth Edition. Chapter 14. Pg 635
 Marshal WJ, Lapsley M, Day A. The Kidneys. Clinical Chemistry.
Elsevier. Eight Edition. Pg 86
 Mohan Harsh. The Kidney and Lower Urinary Tract. Textbook of
Pathology. Jaypee. Seventh Edition. Chapter 20. Pg 636-638
 Pham PT. Renal Manifestations of Sickle Cell Disease. Medscape.
2019. Available from http://emedicine.medscape.com. [Date accessed
July, 2020]

42. References
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 Bukar, A. A., Sulaiman, M. M., Ladu, A. I., Abba, A. M., Ahmed, M. K., Marama, G. T., & Abjah, U. M. (2019).
Chronic kidney disease amongst sickle cell anaemia patients at the University of Maiduguri Teaching
Hospital, Northeastern Nigeria: A study of prevalence and risk factors. Mediterranean Journal of Hematology
and Infectious Diseases, 11(1).

 Yusuf, R., Hassan, A., Ibrahim, I. N., Babadoko, A. A., & Ibinaiye, P. O. (2017). Assessment of kidney
function in sickle cell anemia patients in Zaria, Nigeria. Sahel Medical Journal, 20(1), 21.

 Nnaji, U. M., Ogoke, C. C., Okafor, H. U., & Achigbu, K. I. (2020). Sickle cell nephropathy and associated
factors among asymptomatic children with sickle cell anaemia. International Journal of Pediatrics, 2020.

 Ocheke, I. E., Mohamed, S., Okpe, E. S., Bode-Thomas, F., & McCullouch, M. I. (2019). Microalbuminuria
risks and glomerular filtration in children with sickle cell anaemia in Nigeria. Italian journal of pediatrics, 45, 1-
6.

 BRAIMOH, R. W., Ale, O. K., & Adewunmi, J. A. (2017). Evaluation of urinary tract infection and nephropathy
in adult Nigerians with sickle cell anaemia. Tropical Journal of Nephrology, 12(2), 23-30.

 WHO FIFTY-NINTH WORLD HEALTH ASSEMBLY A59/9 Provisional agenda item 11.4 24 April 2006

 Aeddula NR, Bardhan M, Baradhi KM. Sickle Cell Nephropathy. [Updated 2022 Sep 12]. In: StatPearls
[Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK526017/