1. Sickle cell disease renal manifestations
Dr m.s forghani MD, MUK

2. Overview of SCD
• SCD is one of the most frequent hereditary haematologic diseases in the
world.
• Its most severe and common form, sickle cell anaemia (SCA), results from
homozygosity for the mutant form of the gene that encodes globin.β‑
• SCA is also the most severe form of SCD in terms of its renal
manifestations.
• there are 5 variants of SCD that known as Cameroon, Senegal, Benin,
Bantu, and Saudi-Asian.
• Their clinical importance is because some are associated with higher
HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have
milder disease.
• These renal manifestations are generally less severe in the double
heterozygous forms and SCT

3. pathobiology of sickle cell disease
In kidney medulla Hb S polymerization
is governed by low PH , low PO2, high Osmolality
Abnormal S-RBC membrane
Adhesion receptor
Vasa recta Low blood flow
increase RBC adhesion
to the endothelium

4. Renal vasculopathy in SCD

5. Glomerular hyperfiltration
• This finding indicates that (Increase RPF, RBF,GFR)
glomerular hyperfiltration is driven by increased
glomerular perfusion and increased effective
glomerular filtration surface area, but not by increased
glomerular capillary hydrostatic pressure.
• The investigators found significantly increased GFR
and renal plasma flow in patients with sickle cell
disease versus controls, with a decrease in filtration
fraction (FF), which suggests predominant dilatation
of the efferent arteriole and loss of juxtamedullary
nephrons

6. Acute kidney injury
• AKI occurs in 4–10% of hospitalized patients
with SCD, and is more frequent in patients with
acute chest syndrome (13.6%) than in
patients with painful crisis (2.3%).
• AKI is prognostically important in SCD, as
it predicts a less favourable outcome among
patients who are transferred to the intensive
care unit.

7. Pathogenesis of SCN
Increased renal growth
Increased Na delivery, Na reabsorption, increased PCT metabolic function
(renal enlargement)
Glomerular and other histologic lesions
Capillary congestion, mesangial proliferation, glomerulosclerosis, interstitial
nephritis and fibrosis
Proteinuria
27% of patients in the first three decades, nephrotic syndrome in 4%,
Albuminuria levels >500 mg/g creatinine are associated with progressive
CKD
Chronic kidney disease: 29-42%
vascular, endothelial, tubular, interstitial process interactions
CKD risk factors: PB19, HTN,Hb level, age, PAH

8. Renal manifestations of sickle cell disease
Haemodynamic glomerular injury
 Endothelium–podocyte/pericyte crosstalk
 Haemolysis-induced renal injury
 Urinary concentration defect
 Hematuria
 Distal nephron dysfunction
 Podocyte integrityis critically dependent upon a healthy glomerular endothelium
 Podocyte : VEGF ---> NO
 SFLT1 => Inhibit trophic effect of VEGF on podocyte
 Endothelium : ET-1, TNF => induced podocyte dysfunction and proteinuria
 Endothelial dysfunction: induced procuagolant, poinflammatory phenotype and
might perturb the behaviour of pericytes
 increases wall tension , Increased wall tension might damage the
glomerular endothelium, the podocyte, and the filtration barrier, areas
of the glomerular basement membrane will be bereft of podocyte foot
processes => FSGS

9. Haemolysis-induced renal injury
• HbS is an unstable protein that undergoes autoxidation and
denaturation to produce oxidants and free haem
• Epithelial IRON accumulation
• Heme triggers TLR4 (mesangial, endothelial, epithelial,
podocyte) signaling leading to endothelial cell activation
( proinflammatory and progoagulant phenotype)
• free haem and Hb S: promotes proliferation of smooth
muscle cells , proinflammatory and profibrogenic gens
upregulation in tubulointerstitial and glomerular compartment

10. Urinary concentration defect& Hematuria
Partial Distal RTA in 40% case of SCD

11. Treatment: Hematuria
Hematuria:
• is a common complication of SCN and often self limited in
nature. Conservative measures such as bed rest, to prevent
dislodging of blood clots, and oral hydration are the
preferred treatments.
• Severe cases have been treated with urine alkalinization, to
increase urine flow, and blood transfusion to reduce the
hemoglobin S concentration.

12. Treatment: Proteinuria
• Proteinuria and hypertension should be controlled
• A patient with proteinuria should be started on ACE
inhibitor or ARB, as it can reduce protein excretion by as
much as 50%.
• The blood pressure goal in a patient with proteinuria is less
than 130/80mmHg.
• In SCD patient should avoid the use of diuretics as they
can contribute to intravascular volume depletion and cause a
sickling crisis.
• The addition of hydroxyurea to ACE inhibitoror ARB
therapy might aid in reduction of proteinuria as well.
• NSAIDs should also be avoided as they can reduce the
renal blood flow and depress the GFR.

13. Treatment : Anemia
• Treatment of anemia is common in all chronic kidney disease
patients; however, those with SCD have a lower goal
hemoglobin level.
• Recommendations are to keep hemoglobin levels no higher
than10g/dL an davoid a hematocrit rise of greater than 1–
2% per week. Higher levels of hemoglobin can precipitate a
vasoocclusive crisis.
• Sickle cell patients often require blood transfusions to
maintain this hemoglobin level.
• The use of erythropoietin is not routine in ESRD sickle cell
patients, as it does not have the benefit of increasing the
proportion of healthy hemoglobin A as a blood transfusion
does.

14. ESRD
• The incidence of dialysis-related complications is no
higher in SCD patients than in other ESRD patients.
• After 2 years of hemodialysis, SCD patients and non SCD
patients have “similar rates of mortality”
(33%vs.37%,respectively).
• However, patients with and without SCD on hemodialysis
showed decreased “survival rates” in the SCD
patients at both 3 years and 5 years
(60%vs.80%at3yearsand40%vs.60%at5years).

15. Kidney transplantation
• The 1-year acute rejection rate and graft survival seen in SCD
patients were not significantly different from those receiving kidney
transplant for other causes of renal failure.
• However, the 3-year rates did show a decline in graft survival in
sickle cell patients (48%vs.60% when compared with ethnically
matched kidney recipients).
• The overall survival is also lower than the general population at
both 1 year (78%vs.90%) and 3 years (59%vs.81%).
• Some authors have noted an increase in the frequency of painful
sickle cell crisis after transplantation likely due to the subsequent
rise in hemoglobin post-transplant.