Rituximab in Renal Disease and Transplantation

Salwa Ibrahim, MD FRCP (Edin)Cairo University

The 17th Annual Conference of the Internal Medicine Department30-31 March 2016

Rituximab

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

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

Lupus Nephritis

Induction therapyUncontrolled study

• 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

Uncontrolled studyRefractory cases

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

The study results

• Partial response or complete renal response was observed in 88% after a median of 12 months

• 25% experienced a renal relapse

Double blind randomized controlled study

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

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

Rituximab in LNConclusions

• 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

ANCA Vascuilitis

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)

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

KDIGO 2012

Membranous Nephropathy

• 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

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 monthsRenal function remained stable in the majority of patients

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)

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

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

Mixed cryoglobulinemia

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

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

Rituximab in Renal Transplantation

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

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

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

• 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

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

• 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

All of the candidates initially demonstrated reduced levels of HLA

antibody, but statistical significance was only obtained in one patient

Depletion was transient with observed antibody rebound

None of the patients were transplanted due to persistently high levels of antibody and strong positive crossmatches

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

Acute antibody mediated rejection

• 27 renal allograft patients diagnosed with steroid-resistant antibody-mediated rejection

• 22 of the 27 patients were also treated with plasmapheresisand antithymocyte globulin (ATG)

• These individuals were treated with a single dose of rituximab

• 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/dLand 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

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)

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

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

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

Class II DSA by 63% (p = 0.033)

Adverse risks

Adverse reactions

• Neutopenia

• Thrombocytopenia

• Infusion reactions (bronchospasm, hypotension)

• Infections

• CVS adverse effects

• Progressive multifocal leucoencephalopathy

ONE 375 mg DOSE = $ 4130

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

Thank You