lupus nephritis by dr saddique 2

LUPUS NEPHRITIS; The Full Story!!

Objectives

Types of renal diseases in lupus patients. Review the WHO classification of lupus

nephritis. Rules of treatment. The role of Mycophenolate in DPGN.

Types of renal disease

Glomerular disease Tubulo-interstitial

disease Vascular Drug induced

Quiz

What is the hallmark of DPGN? Subepithelial deposits Subendothelial deposits Mesangeal proliferation Inflammatory cell infiltarte

Class I: normal glomeruliClass II: Purely mesangial disease

a. normocellular mesangium by LM; mesangial deposits by IF &/or EM

b. mesangial hypercellularity with mesangial deposits by IF &/or EM

Class III: Focal proliferative GNClass IV: Diffuse proliferative GNClass V: Membranous GN

a. pure membranousb. with lesions of II (a or b)

Class VI: Chronic sclerosing GN

WHO CLASSIFICATION of LN

Only difference between focal & proliferative GN/LN is amount of endocapillary hypercellularity (proliferative lesions):

focal < 50% glomeruli affected

diffuse> 50% glomeruli affected

Focal Vs Diffuse..!!

WHO Morphological ClassificationRevised 1995

I. Normal glomerulia. normal by all techniques

b. normal on LM but deposits seen on IF or EM

II. Pure Mesangial Diseasea. Mesangial widening, mild hypercellularity, or both

b. Moderate hypercellularity

III. Focal Segmental Glomerulonephritis (GN) (associated with mild or moderate mesangial alterations)

a. Active necrotizing lesionsb. Active & sclerosing lesionsc. Sclerosing lesions

IV. Diffuse GN (severe mesangial, endocapillary, or mesangiocapillary proliferation, &/or extensive subendothelial deposits. Mesangial deposits invariably present & subepithelial deposits often & may be numerous

a. Without segmental lesionsb. With active necrotizing lesionsc. With active & sclerosing lesionsd. With sclerosing lesions


V. Diffuse Membranous GNa. Pure membranous GNb. Associated with lesions of category II (a or B) IV

VI. Advanced Sclerosing GN

NOTE: Lupus renal lesions can change WHO classes over time (either develop a new form of LN after treatment of previous LN or change -------usually progress----to a worse class of LN)


NIH Histologic Scoring System for Activity & Chronicity in LN

Activity Index Chronicity IndexGlomerular Endocapillary hypercellularity

Leukocyte infiltrationFibrinoidnecrosis, karyorrhexisCellular crescentsHyaline deposits, wire loops

Glomerular sclerosisFibrous crescents

Tubulointerstitial Mononuclear cell infiltration

Maximal score 24 12

Rules of Treatment

Treatment of DPGN

Induction therapy

Maintenace of remission

First rule: Kidney Biopsy.

Is it for diagnosis or prognosis?

Why not just start treatment empirically and follow the patient clinically?

Is the kidney biopsy accurate all the time?

First rule: Kidney biopsy

Delaying therapy, because of presumably mild disease, is often associated with increased glomerular injury and fibrosis and therefore a lesser response to immunosuppressive drugs.

The benefit of early treatment with immunosuppressive agents in lupus

nephritis, Esdaile JM et al, J Rheum 1994, 21(11)

First rule: Kidney biopsy

Glomerular hyperfiltration can initially maintain the glomerular filtration rate despite marked nephron loss.

Outcome of the acute glomerular injury in proliferative lupus nephritis.

Chagnac A et al; J Clin Invest 1989 Sep;84(3):922-30

What are the clinical risk factors for progressive

lupus nephritis?

Answer

Clinical risk factors for progression include:

Elevated plasma creatinine concentration at the time of renal biopsy,

Nephrotic-range proteinuria, Anemia with a hematocrit below 26 percent, Black race.

Second rule:No place for prednisone only!

111 patients with active GN randomized to receive IV Cyc, oral Cyc, imuran + Cyc had significantly better preservation of renal function compared to a group received only high dose prednisone. Stienberg AD, A & R,34(8):945-50,1991


Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. Austin HA et al, N Engl J Med 1986 Mar 6;314(10):614-9

Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide. Donadio JV et al, N Engl J Med 1978 Nov 23;299(21):1151-5.


The number of lupus nephritis patients one needs to treat with prednisone and immunosuppressive drugs compared to prednisone alone is 7.6 to prevent one death and 7.8 to prevent one end-stage renal disease.

Bansal et al, Am J Kid Dis, 1997; 29.

Third rule:IV monthly pulses of MP and CYC

A land mark controlled study by NIH of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis.

Boumpas DT et al, Lancet 1992, 26;340(8822):741-5

MP monthly pulses

CYC monthly

CYC monthly with Q3/12 CYC

more effective than 6 months of pulse methylprednisolone in preserving renal function

reduces the rate of exacerbations

Boumpas DT et al, Lancet 1992, 26;340(8822):741-5

Third rule:IV monthly pulses of MP and CYC

Comments: Another report from the NIH compared one year of

monthly pulse MP (1 g/m2 body surface area) to monthly pulse CYC (0.5 to 1.0 g/m2 body surface area for six months and then quarterly) to combination therapy (pulse MP plus pulse CYC).

Again after 5 years of follow up, CYC alone and combination therapy were better than MP alone.

Gourley MF et al, Ann Intern Med 1996 Oct 1;125(7):549-57.

MP monthly for 1Y

CYC monthly, then Q3/12

MP+ CYC monthly then Q3/12

5 years follow up

CYC alone and combination therapy were better than MP alone

Gourley MF et al, Ann Intern Med 1996 Oct 1;125(7):549-57

Extended report After 11 years of follow up, the proportion of patients who had

doubling of serum creatinine concentration was significantly lower in the combination group than in the CYC group.

Both groups were superior to MP alone.

Combination therapy and CYC therapy alone did not differ statistically in terms of effectiveness or adverse events.

Combination therapy with pulse CYC plus pulse MP improves long-term renal outcome without adding toxicity in patients with lupus nephritis.

llei GG et al, Ann Intern Med 2001 Aug 21;135(4):248-57

Fourth rule:CYC is the best!

A meta-analysis concluded that until future RCTs of newer agents are completed, the current use of cyclophosphamide combined with steroids remains the best option to preserve renal function in patients with DPLN. The smallest effective dose and shortest duration of treatment should be used to minimize gonadal toxicity without compromising efficacy.

Treatment of diffuse proliferative lupus nephritis: a meta-analysis of randomized

controlled trials. Flanc RS et al, Am J Kidney Dis 2004 Feb;43(2):197-208

Treatment for lupus nephritis. Cochrane Database Syst Rev 2004;(1):CD002922.

Fourth rule:CYC is the best!

NNT with pulse IV CYC to prevent one death as compared to prednisone alone is 5, and to prevent end-stage renal disease is 6.2.

Bansal et al, Am J Kid Dis, 1997; 29.

Fifth rule:Maintenance regimen. A study by Contreras et al. assessed the role of MMF, AZA and

quarterly intravenous CYC as maintenance therapy in three groups of lupus nephritis patients (mainly classes III and IV) who all received induction therapy with monthly intravenous.

Induction therapy with IV CYC

+

Corticosteroids

CYC IV 0.5-1 gm/m Q3/12

Azathioprine 1-3mg/kg

Mycophenolate 0.5-3 gm/day

The cumulative probability of remaining relapse-free was higher in the MMF (78%) and AZA (58%) groups compared to the CYC group (43%) after a median treatment duration of 29, 30 and 25 months, respectively.

hospitalization, amenorrhoea, infections and gastrointestinal side-effects

Contreras G et al. Sequential therapies for proliferative lupus nephritis. N. Engl. J. Med. 2004; 350

Is this the full story??

Interesting issues:

High versus low dose CYC.

The role of Mycophenolate as a remission inducing agent.

High vs Low dose Cyclophospahamide

The Euro-Lupus Nephritis Trial, Houssiau FA et al, A & R 2002, 46(8):

A prospective clinical trail. To evaluate the efficacy and toxicity of low-

dose IV CYC as a remission-inducing treatment, followed by AZA as a remission-maintaining treatment

High doses IV CYC

(6 monthly pulses+ 2 pulses Q3/12)

Fixed doses of IV CYC at 500mg

(6 monthly pulses)

AZA 2mg/kg/day

41.3 monthsComparable clinical results

Houssiau FA et al. Arthritis Rheum. 2002; 46

Low Infective complications but no

statistical significance

High vs Low dose Cyclophospahamide

Similar results were obtained with an extended observation of the cohort for a further 2 years.

Houssiau FA et al. Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: Lessons from the long-term follow-up

of the Euro-Lupus Nephritis Trial. Arthritis Rheum 2004;50.

What about Mycophenolate? It is used first in lupus nephritis patients in resistant disease.

Randomized control trials:1. Chan TM et al, N. Engl. J. Med. 2000;3432. Chan TM et al, J. Am. Soc. Nephrol. 2001; 12 3. Hu W et al, Chin. Med. J. 2002; 1154. Ginzler EM, Aranow C, Merrill JT, Orloff K, Henry D. Toxicity

and tolerability of mycophenolate mofetil vs intravenous cyclophosphamide in a multicenter trial as induction therapy for lupus nephritis. Arthritis Rheum. 2003; 48 (9 Suppl.): S647

Is this the full story??

The other face of the coin!! The cumulative relapse rate could be up to 44% at

5 years with intravenous CYC therapy. (Ciruelo et al, A&R,1996; 39, Illei GG et al, A&R, 2002; 46, Mok CC et al, A&R, 2004; 50)

Approximately 5-15% of patients with SLE-related diffuse proliferative glomerulonephritis were refractory to CYC. (Valeri A et al, Clin. Nephrol. 1994; 42, Mok CC et al, Am. J. Kidney Dis. 2001; 38)

30-50% still developed doubling of plasma creatinine or end-stage renal disease after 5 years. (Sesso R et al, Lupus 1994; 3, Belmont HM et al, Lupus 1995; 4)

Take home messages

Consider kidney biopsy for abnormal urinary sediment, protienuria, and/or elevated creatinine.

No place for prednisone alone in lupus nephritis. IV MP + IV CYC for severe lupus nephritis. AZA and MMF are effective agents for maintenance

of remission. You may use low doses of CYC as a remission

inducing agent. MMF soon will be a valid option for inducing

remission.

New therapies for lupus nephritis

Blockade of costimulatory molecules; biological agents such as CTLA4-Ig and anti-CD40L monoclonal antibodies used to block the interaction between T cells and B cells.

LJP 394 tolerizes B cells by cross-linking anti-dsDNA surface immunoglobulin receptor on the B cell and triggering the signal transduction pathways that lead to B cell anergy or apoptosis.

New research findings Hydroxychloroquine is an Independent Predictor of Complete

Renal Remission to Initial Mycophenolate Mofetil Therapy in Membranous Lupus Nephritis

Nuntana Kasitanon1, Derek Fine1, Mark Haas1, Laurence Magder2, Michelle Petri1. 1Johns Hopkins University, Baltimore, MD; 2University of Maryland, Baltimore, MD

Methylprednisolone and Cyclophosphamide, Alone or in Combination in Patients with Very Early Lupus Nephritis: A Randomized Controled Trial. Author(s):Juan Antonio Avina-Zubieta1, Griselda Galindo-Rodriguez2, Azucena Ramos3, Reyna Bustamante4, Argelia Perez4, Consuelo Calleja5, Carmen Sanchez6, Carlos Lavalle7 (Combination therapy with IVCy plus IVMP is more effective to achieve and sustain renal remissions )

Cyclophosphamide Therapy for Renal Involvement in SLE: When to Discontinue in Responders? When to Consider it has Failed?Category:27. SLE — treatment and gene therapyAuthor(s):Panayiotis G. Vlachoyiannopoulos1, Michael Samarkos1, Maria Fotia1, Elias Zintzaras2, John Boletis1, Haralampos M. Moutsopoulos1. 1University of Athens, Athens, Greece; 2University of Thessaly, Larissa, Greece Lupus nephritis occurs relatively early following diagnosis of SLE.

Approximately 60% of patients achieve CR with IVCY therapy. More than half of them do so within the first 12 months while CR is unlikely after the 13th CY pulse.

Mycophenolate Mofetil as the Primary Treatment of Membranous Lupus NephritisCategory:27. SLE — treatment and gene therapyAuthor(s):Nuntana Kasitanon1, Michelle Petri1, Mark Haas1, Laurence Magder2, Derek Fine1. 1Johns Hopkins University, Baltimore, MD; 2University of Maryland, Baltimore, MD

Safety and Efficacy of Leflunomide in the Treatment of Lupus Nephritis Refractory to Traditional Immunosuppressive Therapy: An Open-Label TrialCategory:26. SLE — clinical aspectsAuthor(s):Lai-Shan Tam, Edmund K. Li, Chun-Kwok Wong, Christopher W. Lam, Cheuk-Chun Szeto. Chinese University of Hong Kong, Hong Kong, Hong Kong Special Administrative Region of China Presentation Number:444

TNF-Alfa and TNF-Receptors in Biopsy-Verified Lupus NephritisCategory:28. SLE — human etiology and pathogenesisAuthor(s):Iva Gunnarsson, Gouzhong Fei, Stefan H. Jacobson, Johan Frostegård. Department of Medicine; Karolinska Institutet, Stockholm, Sweden

Infliximab Treatment in SLE: Despite Transient Autoantibody Increase Transient Remission of Arthritis and Long-Term Reduction in ProteinuriaCategory:27. SLE — treatment and gene therapyAuthor(s):Martin Aringer, Winfried B. Graninger, Gunter Steiner, Josef S. Smolen. Medical University of Vienna, Austria, Vienna, Austria

What is the defenition of remission?

Answer:

Proteinuria < 500 mg/24h (rarely some recent studies uses < 1gm/24h)

RBC in urine < 5/HPF No RBC casts Normal serum creatinine and estimated GFR

or…..

Is there a relationship between risk of kidney

disease/flare and ANA?

Is there…AntidsDNA level?

Answer:

Progressive Reduction in Risk of Renal Flare in SLE Patients is Associated with Improved Long-Term Control of Anti-dsDNA Antibody LevelsCategory:27. SLE — treatment and gene therapyAuthor(s):Matthew D. Linnik, Tenshang Joh. La Jolla Pharmaceutical Company, San Diego, CA

Thank you

lupus nephritis by dr saddique 2

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