B Thalassemia is a blood disorder caused by reduced or absent beta globin chain production. This leads to anemia and other complications. Patients often require lifelong blood transfusions, which can cause iron overload and damage organs like the heart, liver, and endocrine glands if not treated with chelation therapy. Renal complications can also occur due to iron overload, chronic anemia/hypoxia, or side effects of chelation drugs. Biomarkers show these may include tubular injury, glomerular dysfunction, proteinuria, and reduced GFR. Careful monitoring of renal function is important in managing thalassemia patients long-term.

1. B Thalassemia and Renal complications
MOHAMED ABDELMONEM
MD,MRCP

2. B Thalassemia
 An absence or deficiency of B-chain synthesis of adult HbA
 The molecular defect in B thalassemia result in the absence or
varying reduction (according to the type of mutation ) in B chain
production.
 In individuals with beta thalassemia, there is either a complete
absence of B chain production (B thalassemia major ) or a partial
reduction in B globulin production (B thalassemia minor)

3. Site of synthesis of globin

4. Diagnosing Thalassemia

5. Laboratory study
 Complete blood count and peripheral blood film exam. Are usually
sufficient to confirm the diagnosis.
 Hb level range from 4- 8 gm /dl
 MCV and MCH are significantly low
 Reticulocyte count elevated 5-8 %
 Leukocytosis
 In PBF hypochromasia and microcytosis, polychromatophilic cell,
nucleated red blood cell.
 HPLC (high performance liquid chromatography) confirm the diagnosis

6. PBF: β-thalassemia major
Target cell
Tear drop cell
Elliptocyte
Hypochromic
Microcyte

7. Complications
 Iron overload : From disease itself or from frequent blood transfusions
 Result in damage to the heart, liver and endocrine system
 Bone deformities: Bone marrow expand, result in abnormal bone
structure specially in the face and skull.
 Bone marrow expansion makes bones thin and brittle, increasing the risk of
broken bones.

8. Complications
 Splenomegaly : Thalassemia is often accompanied by the destruction of a large number of red
blood cells and the task of removing these cells causes the spleen to enlarge.
 Splenomegaly can make anemia worse, and it can reduce the life span of the transfused red
blood cells. Severe enlargement of the spleen may require its removal
 Slow growth rates
 Congestive heart failure and arrhythmias
 Infection ( Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis)
 Extramedullary hematopoiesis, Chronic hemolysis
 Psychological complication
 Hypercoagulable disease

9. Features of iron overload
Cirrhosis
Diabetes
Infertility
Pituitary failure
Hypothyroidism
Arrythmia
Heart failure
Dark skin
Liver Heart Endocrine organs

10. Causes of death in thalassemia
 Congestive heart failure
 Arrhythmia
 Sepsis due to increase susceptibility to infection
 Multiple organ failure due to hemochromatosis

11. Thalassemia major-life expectancy:
 Without regular transfusion - Less than 10 years
 With regular transfusion and no or poor iron chelation - Less than 25 years
 With regular transfusion and good iron chelation – 40 years, or longer?
 The commonest cause of death is iron overload

12. Management
 Hematopoitec stem cell transplantation : it is the only known treatment
for thalassemia, however this option is available only to a relatively small
number of patient
 Blood transfusion : should be initiated at an early age, attempt should
made to keep Hb level to 9-10 gm/dl
 Chelation therapy: to overcome overload and iron toxicity. The optimal
time for therapy to start is 1-2 year of transfusion when ferritin level is about
1000-1500 ug /l
 Gene therapy
 Role of surgery in thalassemia

13. Risk stratification for BMT
 Hepatomegaly >3cms
 Liver fibrosis
 Inadequate chelation
 Class I – no risk factors
 Class II- one to two risk factors
 Class III- all three risk factors

14. Outcome of BMT in thalassemia
Guideline- Thalassemia International Federation-2017
Class probabilities of
survival (%)
disease-free
survival (%)
risk of rejection
(%)
risk of mortality
(%
I 93 91 2 8
II 87 83 3 15
III 79 58 28 19

15. Gene therapy
 Insertion of normal globin genes into marrow stem cell may ultimately cure
Thalassemia .
 Globin gene transfer in autologous CD34+cells.
 Reduced or eliminated the need for long term red cell transfusion without serious
adverse events.
 As per FDA recommendation, the current study is restricted to adults. Pediatric
patients will be included at a later date after reviewing safety and efficacy data
obtained in adults
Guideline- Thalassemia International Federation-2014
Guidelines for the Management of transfusion dependent Thalassemia,2017

16. Available iron chelators for the management of trans
fusional iron overload in patients with B-thalassemia
Property Deferoxamine Deferiprone Deferasirox
Usual dosage 25–60 mg/kg per day 75 mg/kg per day 20–40 mg/kg per
day
Route Subcutaneous/ intravenous 8–12 hr, 5
d/wk
Oral, 3 times daily Oral, once daily
Half-life 20–30 min 3–4 h 8 –16 h
Excretion Urinary, fecal Urinary Fecal
Advantages Economic
Improved survival in adherent patients
Decreased cardiac mortality,
especially in combination with
deferoxamine
Ease of
administration
Significant reduction
in hepatic and
cardiac siderosis
Adverse events
common
Local injection site reactions
GI disturbances
Allergic reactions
Reddish-brown urine
GI disturbances
Increased appetite/ weight
gain
GI disturbances
Increased serum
creatinine levels
Rash

17. Property Deferoxamine Deferiprone Deferasirox
rare Ophthalmologic
changes
Auditory disturbance
Aminotransferase elevations
Bone abnormalities
Growth retardation
Cardiovascular events Respiratory
distress Neurologic disturbance
Agranulocytosis
Neutropenia
Aminotransferase
elevations
Arthralgia
Progression of liver
fibrosis
Aminotransferase
Proteinuria
Renal and hepatic
failure
GI hemorrhage
Available iron chelators for the management of trans
fusional iron overload in patients with B-thalassemia

18. Evaluation of iron overload
 Serum ferritin concentration
 Keeping serum ferritin <1000-2,000 ng/mL
 or
 Liver iron concentration (LIC) LIC <15 mg/g dry
weight
 Liver biopsy
 – n=1.8 -7 mg/dry wt , >15-20 mg
 MRI
Guideline- Thalassemia International Federation-2017

19. Role of surgery in thalassemia
 Cholelithiasis – Cholecystectomy
 Choledocholithiasis – Choledocholithotomy
 Cirrhosis (due to iron overload) – Liver biopsy and liver
transplantation
 Leg ulcer – Surgical dressing
 Pathological fracture – Surgical correction
 Spinal cord compression - Laminectomy
Guideline- Thalassemia International Federation-2017

20. Preventative measures
 Immunoprophylaxis:
At least 2 weeks before splenectomy and immunocompromised patients
Pneumococcus/meningococcus/Hemophilus influenza vaccines
 Chemoprophylaxis:
Chemoprophylaxis with life-long oral penicillin.
 Education

21. Mechanisms of renal complications
 Iron overload
 Chronic anemia and Hypoxia
 Iron chelation therapy

22. Iron overload
 Autopsy series on patients with TDT
showed iron deposition in terminal
portions of the proximal tubules and in
the distal tubules.
 Hemosiderin deposits may pave the way
for tubular necrosis, cortical atrophy, and
interstitial fibrosis, which could be a factor
in both acute and chronic kidney injuries
in thalassemia

23. Chronic anemia and Hypoxia
 Renal tubular cells can equally be
exposed to oxidative stress and lipid
peroxidation from states of chronic
hypoxia and anemia, even without iron
overload.

24. Iron chelation therapy
 Oral deferiprone (DFP)
Deferasirox (DFX),
Parenteral deferoxamine (DFO)
 Kidney injury is a prominent side effect with DFX and
DFO, especially when tight dosage monitoring is absent.
Increased urinary excretion of beta-2 microglobulin and
growth hormone after continuous DFO infusion suggests
a role for over-chelation.

25. Mechanisms of renal disease in patients with B-
thalassemia

26. Glomerular injury
 Changes in GFR
 Glomerular hyperfiltration can range from 20 to 40% of thalassemia cases.
 Albuminuria
 In pediatric TDT patients, proteinuria ranged from 24% to 47%, and did not
change with deferoxamine therapy.
 Significant glomerular proteinuria in adult patients was 20% using ACR
 ICT-mediated acute kidney injury
 This mostly occurred with the intravenous method of administration
following overdose of the drug due to malfunction of the pump and/or
inadequate monitoring during treatment.

27. Glomerular injury
 Renal hemosiderosis
 End stage renal disease
 In a cohort of 127 NTDT patients, 4% developed ESRD that required regular hemodialysis. A
review of their medical charts over a 10 years observation period revealed that elevations in
serum creatinine and dipstick-positive albuminuria were the first manifestations of renal
disease
 Fanconi sydrome
 Renal wasting of electrolytes, amino acids and glucose occurs in thalassemia, and it is most
likely a tubular dysfunction
 Urolithiasis
 Transfusion-dependent thalassemia patients have a higher occurrence of both
asymptomatic (59%) and symptomatic (18%) kidney stones compared to the general
population.

28. Guidance for management of renal issues with iron
chelation therapy
Issue Deferoxamine Deferiprone Deferasirox
Pre-cautionary Monitor patients for
changes in renal
function
Special care must be
taken in patients with
renal impairment since
studies have not been
conducted to evaluate
its safety
and efficacy in these
patients
Measure serum
creatinine and Cr Cl
before
starting therapy; Monitor
serum creatinine
regularly
Baseline renal
impairment
Contraindicated in
patients with severe
renal disease or anuria
DFP has not been
evaluated in patients
with renal impairment
Impairment of Cr Cl 40–
60 mL/min: reduce
starting dose by 50%; do
not use if serum
creatinine >2× or Cr Cl
<40 mL/min

29. Guidance for management of renal issues with iron
chelation therapy
Issue Deferoxamine Deferiprone Deferasirox
Increased
serum
creatinine
Monitor patients for changes in
renal function; increased serum
creatinine, acute renal failure,
and renal tubular disorders
have been reported in post
marketing studies
(No guidance
provided)
Treatment should be
interrupted or reduced if
increase is >33% above
baseline at 2 consecutive visits
(and above the age-
appropriate ULN in pediatric
patients)
Continued renal
impairment
(No guidance provided) (No guidance
provided)
Discontinue therapy if Cr Cl<40
mL/min, or serum
Creatinine >2×

30. Renal Biomarkers Range of frequency (%)
Markers of renal tubular injury
Hyper phosphaturia 0-9.2
Hypercalciuria 0-79.2
Aminoaciduria 5.9-31.4
Magnesiumuria 8.6
Urinary 2-Microglobulin 0-64.6
Elevated FENa 0-29.1
Urinary N-acetyl- -D-glucosaminidase (NAG) 35.9-100
Elevated Serum 2-Microglobulin 5
Elevated urinary retinol binding protein (RBP) 69.4
Elevated urinary alpha-1 Macroglobulin 54.8
Decreased urinary osmolarity 58.1-100
Frequency of positive renal biomarkers throughout studies
in TDT, organized by renal injury types.

31. Markers of glomerular injury and GFR
Elevated serum Cystatin-C 33.2-50
Glomerular hyperfiltration by eGFR 17.8-39.6
Decreased eGFR 0-58.82
Mixed glomerular/Tubular injury
Proteinuria 0-90
Microalbuminuria 0-100
Others
Hematuria 3.4-10.6
Frequency of positive renal biomarkers throughout studies in TDT,
organized by renal injury types.

32. Conclusions
 Renal disease is a long-term complication that should be recognized in
thalassemia, especially with the rise in the average age of this population.
 Proper assessment of renal function abnormalities in thalassemia can be
challenging because of the increased use of iron chelators, which
themselves can affect renal function.
 With increasing information concerning the renal abnormalities and
convenient renal biomarkers, good meta-analyses can shed light on the
best tools to use for assessment and prevention of renal disease in
thalassemic patients.
 Progress of research in this topic will allow the detection of renal
dysfunction harbingers in hope to arrest the progress of renal injury, if not to
reverse it.

33. Thank You