Rituximab is a monoclonal antibody that depletes B cells and has been used to treat various immune-mediated renal diseases and in transplantation. It has shown benefits in refractory lupus nephritis, membranous nephropathy, and cryoglobulinemia in observational studies. However, randomized controlled trials in lupus nephritis did not show a significant benefit of rituximab over standard therapies. Rituximab has also been used successfully in ABO-incompatible and desensitization protocols in renal transplantation to reduce antibody levels, though trials on desensitization showed transient effects. Rituximab may improve outcomes for severe antibody-mediated rejection. Further large randomized trials are still

1. Rituximab in Renal Disease and
Transplantation
Salwa Ibrahim, MD FRCP (Edin)
Cairo University
The 17th Annual Conference of the Internal Medicine Department
30-31 March 2016

2. Rituximab
A monoclonal
chimeric antibody
directed against
CD20, induces a
profound and long-
lasting mature and
immature B cell
depletion

3. It has been used in immune diseases that are thought to be B
cell mediated
• It has been used in lupus nephritis, membranous
nephropathy, steroid dependent and resistant nephrotic
syndrome, cryoglobulinemic vascuilitis, ANCA associated
vascuilitis
• Rituximab has been used to treat antibody mediated
rejection, and to block antibody production prior to ABO
incompatible transplantation

4. Lupus Nephritis

5. Induction therapy
Uncontrolled study

6. • 20 patients received rituximab
as induction treatment for an
active class IV or class V lupus
nephritis
• After a median follow-up of 22
mo, complete or partial renal
remission was obtained in 12
patients (60%)
• Rapidly progressive
glomerulonephritis did not
respond to rituximab

7. Uncontrolled study
Refractory cases

8. The study design
• 25 patients with refractory LN were treated with RTX in
combination with i.v. CYC and glucocorticoids
• RTX 375 mg/m2 was given once weekly for 4 weeks
• CYC 0.5 g i.v. was given in combination with the first and
fourth RTX infusion

9. The study results
• Partial response or
complete renal response
was observed in 88% after
a median of 12 months
• 25% experienced a renal
relapse

10. Double blind randomized
controlled study

11. The LUNAR study design
• The study investigated whether the addition of rituximab to a
background of MMF plus corticosteroid in patients with
proliferative LN could improve renal outcome at 52 weeks
• Patients with class III or class IV lupus nephritis were randomized to
receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and
182
• The primary end point was renal response status at week 52

12. The overall (complete and partial) renal response rates were
45.8% among the 72 patients in the control group and 56.9%
among the 72 patients receiving rituximab (P: 0.18)
The primary end point (superior response rate
with rituximab) was not achieved

13. Rituximab in LN
Conclusions
• Rituximab is not currently indicated or
approved by the FDA or the KDIGO for
induction of Remission in Lupus
Nephritis
• Observational studies of Rituximab
therapy shows “beneficial” effects in
“Refractory” or “Relapsing” LN but
relapses common
• No benefit in RPGN with crescents

14. ANCA Vascuilitis

16. A prospective open-label pilot trial
• 10 patients with active severe ANCA - vasculitis, and resistance
to (or intolerance of) cyclophosphamide
• The regimen consisted of oral prednisone (1 mg/kg/d) and
four weekly infusions of rituximab (375 mg/m2)

17. There was significant decrease in serum creatinine, ESR, CRP, C-ANCA at 6 months

18. KDIGO 2012

19. Membranous Nephropathy

20. • Current treatment options recommended by KDIGO include
corticosteroids, alkylating agents, cyclosporin A,
mycophenolate mofetil, and tacrolimus
• Their use may be associated with significant adverse effects
and is not effective in all patients

22. The study design
• 15 patients with persistent IMN with rituximab 1 g i.v. on days
1 and 15
Proteinuria decreased from 13.07 g per 24 h to 6.077.3 g per 24 h at 12 months
Renal function remained stable in the majority of patients

24. The Study Design
• A Prospective, observational study evaluated the 1-yr
outcome of 8 IMN patients with persistent urinary protein
excretion 3.5 g/24 h and mild to moderate renal insufficiency
• 4 weekly infusions of rituximab (375 mg/m2)

25. At 12 months, proteinuria significantly decreased from mean 8.6
to 3.0 g/24 h (P < 0.005) (60% reduction)

26. Conclusions of RTX in IMN
• There is no current evidence to support its use as a primary
agent in IMN
• Rituximab can be used in severe or refractory cases with mild
to moderate renal insufficiency

27. Mixed cryoglobulinemia

28. Mixed cryoglobulinemia
• Immune complex mediated small to medium vessel vasculitis associated
with neuropathy, arthritis, rash and proliferative glomuronephritis
• HCV triggers B-cell expansion with production of IgG-IgM cryoglobulins
• Antiviral therapy, steroid, cyclophosphamide and plasma exchange are
commonly used in HCV related cryoglobulinemia

30. Multicenter retrospective study
• 87 HCV patients with active cryoglobulinemic vascuilitis
treated with rituximab monotherapy 375 mg/m2 weekly x
4doses and followed up for 6 months
24-hour proteinuria and serum creatinine significantly
improved after rituximab treatment

31. Rituximab in Renal Transplantation

32. ABO incompatible renal transplantation
• In the early days of ABOi, splenectomy was considered
mandatory
• Rituximab has replaced splenectomy to reduce ABO antibody
titers together with IA
• Single dose of 375 mg/m2 is used widely in Japan and across
Europe

33. 74 ABO-i recipients were treated with this protocol, and all patients
underwent kidney transplantation successfully. The Patient survival rates
were 95%

34. RTX has been used for desensitization therapy in highly sensitized
recipients undergoing renal transplantation

35. • 20 patients were highly HLA-sensitized and had donor-specific
antibodies on the waiting list for a kidney transplant
• IVIG given twice (2 g/kg) on day 0 and day 30
• Rituximab given twice (1 g) on day 7 and day 22

36. PRA decreased significantly after second rituximab infusion (P<0.001)

38. • Five renal transplant candidates with PRA 50-100%
• IVIG 2g/kg on day 0 and 30
• Rituximab 1 gm IV on day 7 and 21

39. All of the candidates initially demonstrated reduced levels of HLA
antibody, but statistical significance was only obtained in one patient

40. Depletion was transient with observed antibody rebound
None of the patients were transplanted due to persistently
high levels of antibody and strong positive crossmatches

41. Conclusions of the previous studies
• Evidence of limited quality was identified to support the use
of rituximab desensitization in highly sensitized recipients
• Further randomized controlled trials are required to better
define the efficacy, long-term safety, and optimal dosing
regimen of rituximab in this setting

42. Acute antibody mediated rejection

44. • 27 renal allograft patients diagnosed with steroid-resistant
antibody-mediated rejection
• 22 of the 27 patients were also treated with plasmapheresis
and antithymocyte globulin (ATG)
• These individuals were treated with a single dose of rituximab

45. • 3 Patients experienced graft loss during the follow-up period
• In the 24 successfully treated patients, the serum creatinine
at the time of initiating rituximab therapy was 5.6 ± 1.0 mg/dL
and decreased to 0.95 ± 0.7 mg/dL at discharge
• The addition of rituximab may improve outcomes in severe
steroid-resistant antibody-mediated rejection episodes after
kidney transplantation

46. Chronic antibody-mediated rejection
• CAMR is the major cause of late renal
allograft loss
• It is a continuous process associated
with fluctuating levels of de novo DSA
• The diagnostic criteria of CAMR include
(i) defined morphological features
including transplant glomerulopathy
(ii) diffuse C4d deposition in PTC
(iii) the presence of donor-specific
antibody (DSA)

48. The treatment regimen
• Four weekly doses of IVIG (1 g/kg body weight per dose),
followed by a single dose of rituximab (375 mg/m2) 1 week
after the last IVIG infusion
• Loss of eGFR decreased significantly from 7.6 ml/min/1.73
m2 during 6 months prior to treatment to 2.1 ml/min/1.73
m2 (P = 0.0013) during 6 months after treatment

49. During 2 years of follow-up, the median loss of eGFR remained significantly
lower compared with prior to AHT

50. Class I DSA declined by 61% (p = 0.044)

51. Class II DSA by 63% (p = 0.033)

52. Adverse risks

53. Adverse reactions
• Neutopenia
• Thrombocytopenia
• Infusion reactions (bronchospasm,
hypotension)
• Infections
• CVS adverse effects
• Progressive multifocal
leucoencephalopathy
ONE 375 mg DOSE = $ 4130

54. Conclusions
• Rituximab is an anti-CD 20 monoclonal antibody that leads to long
lasting B cell depletion
• It has been licensed for treatment of non-Hodgkin lymphoma and
rheumatoid arthritis
• It is widely used in ABO incompatible renal transplantation, and is
used as alternative therapy in treatment of membranous
nephropathy, refractory lupus nephritis, cryoglobulinemia and
steroid dependent nephrotic syndrome with mixed results
• Further RCTs with large study population are still needed to confirm
its efficacy in the field of renal transplantation

55. Thank You