Pathogenesis Clinical Manifestation Pathological ... · Nephrology Board Review 19 /0757 Thaweepong...

Nephrology Board Review 19/07/57

Thaweepong Pajareya M.D. 1

Thaweepong Pajareya M.D.

Director,

Department of Pathology,

Bhumibol Adulyadej Hospital

Nephrology Board Review

19 July 2014

TOPIC

• Pathogenesis

• Clinical Manifestation

• Pathological Classification

• Therapeutic options



CAUSES OF DEATH IN SLE

1950 –1955

1956 –1962

1963 –1973

1973 –1987

1978 -2008

Patients 491 491 491 389 500

All deaths (%)

12 20 19 22 15

Death from nephritis (%)

26 36 14 4 8

Death from infections (%)

16 12 18 39 25

Rahman A et al. In Lupus Nephritis , second edition. 2011. 35 – 58.



Antigen specificity Prevalence (%)

Anti dsDNA 70 – 80

Nucleosomes 60 -90

Sm 10 – 30

α - Actinin 20

C1q 40 - 50

PATHOGENIC AUTOANTIBODIES IN SLE

Rahman A et al. N Engl J Med. 2008;358:929 – 39.

NUCLEOSOMES



INDUCTION OF SURFACE BLEB DURING APOPTOSIS

Autoimmune 2012



SYSTEMIC LUPUS ERYTHEMATOSUS

• Systemic autoimmune disorder characterized by a striking predominance and frequently development of glomerulonephritis

• Renal involvement in SLE remains the strongest predictor of overall patient morbidity and mortality



RENAL INVOLVEMENT IN SLE

• 20 – 49 % of patient during their course

• 40 – 60 % of LN patients develop during first manifestation

•More frequent in children, male , African American , Hispanics

KIDNEY INVOLVEMENT IN SLE

• Incidence differs with ethnicity

• Caucasians 12 – 33%

• African American 40 – 69 %

• Hispanic 36 – 61 %

• Asian 47 – 53%



RENAL MANIFESTATIONS OF LUPUS

• Proteinuria

• Present in almost every pts. with nephritis

• Often sufficient to be associate with some degree of edema

• May come and go spontaneously

• Severe lupus nephritis is unusual in the absence of proteinuria

Ropes, Medicine; 1964, 43, 387-391


• Nephrotic syndrome

• 25% of all pts. with LN will show a nephrotic syndrome at some time in their disease course

• More common in ISN/RPS class III , IV and V

• Hematuria

• Microscopic hematuria is common, macroscopic hematuria is very rare

• Cast

• Present in about 1/3 of patients

• Granular cast , rbc cast




• Hypertension

• 25 - 50% of patients were assessed as hypertensive

• Those with more severe nephritis were more commonly hypertensive (class II 17%; class IV 55% )

• HT is not often of great severity, retinopathy is usually mild; and accerelated HT is rare

RENAL MANIFESTATION IN SLE

• Abnormal Urinary abnormality

• Nephrotic syndrome

• Acute glomerulonephritis

• Rapidly progressive glomerulonephritis

• Thrombotic microangiopathy



WHEN TO TREAT ?

HOW TO TREAT ?

RISK FACTORS FOR ESRD

• Clinical characteristic

• Elevated initial serum creatinine *

• Nephrotic range proteinuria

• Low C3

• Hematocrit < 26 %

• Hypertension *

• Persistent disease activity

Berden JHM: Lupus nephritis, KI 1997,52:538-558




• Demographic characteristics

•Male gender

• Black race

• Age < 24

• Low socioeconomic status



• Treatment characteristics

• No normalization of elevated creatinine

• Treatment with prednisolone only

• Histologic characteristics

•WHO Class IV *

• Activity index > 12

• Chronicity index > 3




ISN/RPS CLASSIFICATION (2003)

• Class I Minimal mesangial lupus nephritis

• Class II Mesangial proliferative lupus nephritis

• Class III Focal lupus nephritis

• Class IV Diffuse segmental (IV-S) or global (IV-G) lupus nephritis

• Class V Membranous lupus nephritis

• Class VI Advanced sclerosing lupus nephritis

Weening JJ et al. Kidney Int 65: 521 – 530. 2004

Class I Minimal mesangial LN



Class II Mesangial proliferative LN

Class III Focal LN



Class IV Diffuse LN



Class IV-G Diffuse Global LN



Class V Membranous Lupus



CLINICAL MANIFESTATIONS OF LUPUS NEPHRITIS

Classification Inciden

ce

Active

urinary

sedime

nt

Proteinu

ria

Nephro

tic

syndro

me

Renal

insufficie

ncy

5-Yr.

renal

survival

I. Minimal < 5 % 0 0 0 0 100 %

II. Mesangial 15 % < 25 % 25–50 % 0 < 15 % > 90 %

III. Focal

lupus

nephtiris

20 % 50 % 67 % 25–33 % 10–25 % 85–90

%

IV. Diffuse

lupus

nephritis

50 % 75 % > 95 % 50 % > 50 % 60–90

%

V.

Membranous

15 % 50 % > 95 % 90 % 10 % 70–90

%

DIAGNOSIS OF LUPUS NEPHRITIS

• At present , there is not any laboratory investigation that is sensitive and specific enough for diagnosis class of Lupus Nephritis

• Lupus nephritis class must be confirmed by kidney biopsy



APPROACH

•Mild

• Proteinuria < 1 gm/24 hr

• Inactive urinary sediment

• Serum creatinine < 1.2 mg/dl (eGFR> 60 ml/min)

• Normotension

• Most likely Class I or II

• Treat extrarenal , follow up

APPROACH

• Severe

• Proteinuria > 1 gm/24 hr

• Serum creatinine > 1.2 mg/dl (eGFR < 60 ml/min)

• Usually active urinary sediment , hypertension

• Most likely Class IV , III

• Need aggressive treatment

• Kidney biopsy helpful



APPROACH

• Moderate

• Proteinuria > 1 gm/24 hr

• Serum creatinine < 1.2 mg/dl (eGFR > 60 ml/min)

• Possibly Class II , III , IV, V

• Kidney biopsy recommended to pick up severe lupus nephritis

• Class III

• Class IV

ขอ้บง่ชีใ้นการตรวจชิน้เนือ้ไต

• เพือ่ยนืยันการวนิจิฉัยโรคในรายทีม่ภีาวะไตอักเสบและสงสยัเป็น

โรคลปัูส แตม่เีกณฑก์ารวนิจิฉัยโรคลปัูสไมค่รบตาม ACR criteria

• เพือ่วางแผนรักษาในรายทีม่โีปรตนีในปัสสาวะมากกวา่ 1 กรัมตอ่วนั

• เพือ่วางแผนรักษาในรายทีม่ี active nephritic urine sediment

[เพือ่วางแผนรักษา ในรายทีต่รวจพบม ีproteinuria > 0.5 กรัม/วนั

รว่มกับม ีnephritic urine sediment (RBC > 5/HPF หรอื RBC

cast)]

• เพือ่วางแผนรักษาในรายทีต่รวจพบการท างานของไตผดิปกตแิบบ

เฉียบพลันทีไ่มท่ราบสาเหตุ

(ร่าง) ค าแนะน าในเวชปฏิบัต ิส าหรับการดแูลรักษาผู้ ป่วยโรคไตอักเสบลูปัสในประเทศไทย สมาคมโรคไตแห่งประเทศไทย 2557



ขอ้บง่ชีใ้นการตรวจชิน้เนือ้ไต

• เพือ่วางแผนรักษาในรายทีไ่ดรั้บ prednisolone

มากกวา่ 8 สปัดาหแ์ลว้ยังไมต่อบสนองตอ่การ

รักษา (ไมเ่ขา้สู ่complete response)

• เพือ่วางแผนรักษาในรายทีไ่ดรั้บการรักษาแลว้แต่

ยังมกีารท างานของไตผดิปกต ิเพือ่แยกระหว่าง

พยาธสิภาพทียั่งอยูใ่นระยะเฉียบพลัน (active)

กบัรอยโรคเกา่ในการอกัเสบเรือ้รัง (scar)


TREATMENT

• No definitive cure in SLE

• Major aim of treatment

• Reduce symptoms

• Halt progression of disease

• Balancing between benefit and risks

• Infection must be excluded prior to institution of corticosteroids or cytotoxic drugs

• Pregnancy : contraception

• Need individualized , flexible approach



TREATMENT OF LUPUS NEPHRITIS

• Class I (minimal-mesangial LN) treat extrarenal

• Class II (mesangial proliferative LN)

• Proteinuria < 1 g : treat extrarenal

• Proteinuria > 3 g : treat as MCD with steroid or CNIs

KDIGO guideline for lupus nephritis. Kidney Int. 2012

TREATMENT OF CLASS III AND IVLUPUS NEPHRITIS

• Severe lupus nephritis requires four distinctly organized therapeutic strategies

Assessment of the systemic disease

Treatment of the acute phase of severe lupus nephritis (Induction therapy)

Maintenance phase (Prevent replase)

Treatment of exacerbation of lupus glomerulonephritis (Flare)



TREATMENT OF LUPUS NEPHRITIS IN 2002

• If the patient had mild FPLN or severe DPLN they got monthly IV cyclophosphamide (IVCY)

• If the patient was follow by a nephrologist or rheumatologist they got monthly IVCY

• If the patient was adult or pediatric they got monthly IVCY

TREATMENT OF LUPUS NEPHRITIS IN 2002

• If the patient had prior IVCY with or without side effects the got monthly IVCY

• Everything was based on small randomized trials many from the US-NIH



NIH LANDMARK STUDY

• Austin III HA et al. NEJM, 1986;314 : 614

• Steinberg AD, et al Arthritis Rheum 1991; 34, 945 – 950.

• Boumpas DT et al, Lancet 1992;340: 741 –745.

• Gourley et al. Ann Intern Med 1996; 549 – 557.

• Illei GG et al. Ann Intern Med 2001; 135: 248 –257.

Steinberg AD, Steinberg SC. Arthritis Rheum 1991; 34: 945-950.

NIH STUDY



NIH REGIMENTREATMENT OF PROLIFERATIVE LUPUS

NEPHRITIS

• Immunosuppressive therapy

• Prednisolone (0.5 – 1 mg/kg/d) for up to 8 weeks,

then taper (by 5 mg qod each week) to 0.25

mg/kg/qod

• Pulse methylprednisolone (1 g/m2/d for 3 days

followed by 1 g/m2/monthly for 6 to 24 months

• Pulse cyclophosphamide 0.5 – 1 g/m2 monthly for

6 months then quarterly for one year beyond

remission

Austin HA, Balow JE. Semin Nephrol, No 1, 1999: 2 – 11

DOWNSIDE IVCY

•Remission rate 60 – 70 %

•Toxicity : Herpes zoster 25%, severe infection 26%, ovarian failure 52%, avascular necrosis



NEWER THERAPY

•More efficient

•Less toxicity

EURO – LUPUS NEPHRITIS TRIAL (ELNT)

• Multicenter prospective clinical trial of 90 LN pts with proliferative LN

• High dose IVCY (6 monthly + 2 quarterly pulses) vs Low dose IVCY (500 mg q2wks x 6)

• Maintenance : AZA (2mg/kg/d) 2 wksafter IVCY

• Follow 41 months

Houssiau et al. Arthritis & Rheumatism 46: 2121 – 2131, 2002.



PROBABILITY OF REMISSION

LD

HD


FREE OF RENAL FLARE

LD

HD




FREE OF SEVERE INFECTION

LD

HD


10 YEARS FOLLOW UP (ELNT)PATIENT SURVIVAL

Houssiau FA et al. Ann Rheum Dis;69: 61 – 64. 2010



COMMENT

•Not exactly NIH regiment : use AZA as maintenance

• Less severity patients compare with NIH

•Mostly Caucasians

MYCOPHENOLATE MOFETIL(MMF)

• Blocks proliferation of both B and T cells

• Inhibits antibody formation and the generation of cytotoxic T cells

• Decreases expression of adhesion of adhesion molecules on lymphocyte and endothelial cell reduction in endothelial –lymphocyte interactions

• Anti – proliferative effect

• Selective antimetabolite



MMF LANDMARK STUDY

• Chan TM, et al. NEJM 2000;343:1156 – 62.

• Chan TM, et al. J Am Soc Nephrol. 2005; 16:1076 – 1084.

• Contreras G, et al. NEJM. 2004;350:971 – 80.

• Ginzler EM, et al. NEJM 2005;353:2219 – 28.

• Apple GB et al. J Am Soc Nephrol. 2009; 20:1103 –12.

• Dooley MA et al. N Engl J Med. 2011; 365:1886-95.

MMF IN LUPUS NEPHRITIS

• Induction of remission

•Maintenance therapy of severe lupus nephritis

• Treatment of refractory case



MMF FOR INDUCTION TREATMENT

• RCT, 42 patients

• Inclusion criteria

• SLE criteria by ARA

• Renal biopsy show diffuse proliferative lupus nephritis (Class IV)

• Proteinuria > 1 gm

• Serum albumin < 3.5 g/dl

Chan TM et al. NEJM. 2000. Vol 343 :1156 - 1162

RESULTS

MMF vs Oral CYC for induction

Chan TM et al. NEJM. 2000.

343 :1156 - 1162



MMF vs Oral CYC for induction

Chan TM et al. NEJM. 2000.

343 :1156 - 1162

LONG TERM STUDY OF MMF

•Median follow up 63 months

• N = 62, 32 MMF, 30 CTX-AZA

• Comparable long-term efficacy compare with oral CTX-AZA regarding renal

preservation and prevent relapse

• Significant reduce unfavorable outcome (Infection and amenorrhea)

Chan TM et al. JASN 16: 1076 – 1084. 2005



MMF VS IVCY IN SEVERE LN(US STUDY)

• Randomized induction trial – patients

with active LN (WHO class III, IV, V)

• 24 weeks , induction period

• 140 pts, 71 MMF, 69 IVCY

•MMF : Target dose 3 g/day

• IVCY : NIH regimen (monthly for 6

months)

Ginzler EM, Dooley MA, et al. N Engl J Med 2005; 353: 2219 – 28.

RESULT

MMF IVCY P value

Complete remiss.

22.5 % 5.8 % 0.005

Partial remiss.

29.5 % 24.6 % 0.51

No remission

47.9 % 69.6 % 0.01



ADVERSE EVENTS

MMF

(N = 83)

IVCY

(N = 75)

Severe infection 1 6

Diarrhea 15 2

Lymphopenia 18 28

Amenorrhea 0 2

US STUDY

•MMF are more effective than IVCY for induction treatment

•MMF has more favorable safety profile

•Comment

• Very low CR in IVCY group

Ginzler EM, Dooley MA, et al. N Engl J Med 2005; 353: 2219 – 28.



MMF VS IVCY FOR INDUCTIONASPREVA LUPUS MANAGEMENT STUDY

GROUP (ALMS)

• International randomized controlled trial

• 370 LN class III, IV, V

• 185 IVCY (0.5 – 1 g/m2 ) monthly pulse

• 185 MMF titrate to 3 g/day

• Duration 24 weeks

• Prednisolone 60 mg/d titrate down

Apple GB, Contreras G, Dooley MA et al. J Am Soc Nephrol 2009;20:1103 – 12.

ALMS

Apple GB, Contreras G, Dooley MA et al. J Am Soc Nephrol 2009;20:1103 – 12.

No different between MMF and IVCY in induction Rx



TREATMENT OFLUPUS NEPHRITIS

Class III LN (focal LN) and class IV LN (diffuse LN) initial therapy

We recommend initial therapy with corticosteroids (1A), combined with either cyclophosphamide (1B) or MMF (1B).

We suggest that, if patients have worsening LN (rising SCr, worsening proteinuria) during the first 3 months of treatment, a change be made to an alternative recommended initial therapy, or a repeat kidney biopsy be performed to guide further treatment. (2D)


MAINTENANCE TREATMENT FOR PROLIFERATIVE LN



SEQUENTIAL THERAPY FOR PROLIFERATIVE LN IVCY INDUCTION IVCY VS AZA VS MMF MAINTENANCE

• N = 59 > 90% F 33 yo 50 % African american

•WHO III = 12, WHO IV = 46, WHO V = 1

• HT 95 %, Active serology

• NS 65 %, Albumin 2.7 g/dl, U Prot > 5g/d

• SCr. 1.6 mg/dl

Contreras G, et al, N Engl J Med; 350, 971 – 80. 2004

TREATMENT

• Induction : Monthly IVCY (500 – 1 g/m2) 4 – 7 doses with steroids

•Maintenance

• Quarterly IVCY : 20 pts

•MMF (500 – 3000 mg/d) : 20 pts

• AZA (0.5 – 3 mg/kg/d) : 20 pts




IVCY

AZA

MMF

PATIENT SURVIVAL


IVCY

AZA

MMF

EVENT-FREE SURVIVAL




IVCY

AZA

MMF

RELAPSE FREE SURVIVAL


SIDE EFFECTS

Hosp D/pt yr

(%)Amenorrhea

(%)

Infection

(%)

Major

(%)

IVCY 13 32 68 12

AZA 1* 7.5* 28* 3

MMF 1* 6.1* 21* 3


Maintenance MMF and AZA

associated with

significant less hospital

days, amenorrhea and

infections than IVCY



MAINTAIN STUDY

• 105 patients with proliferative lupus

• Induction (Euro lupus)

• Pulse MP 750 mg/d for three days

• Oral Pred 0.5 mg/kg/day

• IVCY 500 mg /2 week x 6

• Maintenance

• AZA 2 mg/kg/d

• MMF 2 g/day

Houssiau FA et al. Ann Rheum Dis ; 69:2083 – 2089. 2010

MAINTAIN NEPHRITIS TRIAL

Adverse event are comparable

AZA

MMF

Houssiau FA et al. Ann Rheum Dis ; 69:2083 – 2089. 2010



ALMS MAINTENANCE TRIAL

• 370 patients from ALMS induction trial

• LN Class III, IV, V

• 227 response to induction treatment random to maintenance phase

• 116 : MMF 2 g/day (min: 1 g/day)

• 111 : AZA 2 mg/kg/day (min: 50 mg/d)

• All receive pred 10 mg/day

• Follow 36 months

Dooley MA, et al. N Engl J Med 2011;365:1886-95.

TREATMENT FAILURE


MMF

AZA

P = 0.003



RENAL FLARE


MMF

AZA

P = 0.03

MAINTENANCE THERAPY

•We recommend that, after initial therapy is complete, patients with class III and IV LN receive maintenance therapy with azathioprine (1.5–2.5 mg/kg/d) or MMF (1–2 g/d in divided doses), and low-dose oral corticosteroids (< 10 mg/d prednisone equivalent). (1B)




RECOMMENDATIONSEVERE LUPUS NEPHRITIS

• RPGN or multiorgan: NIH

•Others

MMF induction

Euro Lupus

NIH induction

•Maintenance

MMF or AZA

TREATMENT OF CLASS V LUPUS NEPHRITIS



TREATMENT OF LN CLASS VPRED VS IVCY VS CYA

Austin HA et al. J Am Soc Nephrol. 20:901-911. 2009

42 LMN, NS

Pred AD

Pred + IVCY AM x 6

Pred + CyA

CyA : relapse

INDUCTION IN CLASS V LN

• Pool analysis of ALMS and US study

• IVCY vs MMF for induction

• 84 Class V LN (Mostly Nephrotic)

Radhakrishnan J et al. Kidney Int. 77:152 – 160. 2010



CLASS V TREATMENT

• Only in nephrotic patient

• Prednisolone 0.5 mg/kg/day plus

•MMF

• Cyclosporine

• Pulse IVCY

GENERAL TREATMENT

•We suggest that all patients with LN of any class are treated with hydroxychloroquine (maximum daily dose of 6–6.5 mg/kg ideal body weight), unless they have a specific contraindication to this drug. (2C)



ขอ้บง่ชีใ้นการสง่ปรกึษาอายรุแพทยโ์รคไต

• ยนืยันการวนิจิฉัยโรคไตอกัเสบลปัูส ในกรณีทีม่ขีอ้

สงสยั

• ประเมนิความรนุแรงของโรคไตอกัเสบลปัูส

• วางแผนรักษาโรคไตอกัเสบลปัูส โดยเฉพาะผูป่้วยทีม่ ี

nephrotic range proteinuria หรอืมกีารท างานของไต

ผดิปกต ิหรอืไมต่อบสนองตอ่การรักษา

• รว่มตดัสนิใจและวางแผนการรักษาในภาวะพเิศษบาง

กรณี ไดแ้ก ่การตัง้ครรภ ์และการวางแผนผา่ตดั เป็นตน้


TREATMENT OF LN IN 2014

• Treatment is divided into and induction and maintenance phase

• Induction therapy consists of Euro lupus regimen of IVCY or MMF

• Maintenance therapy consists of MMF or AZA

• New therapies include Rituximab based and corticosteroid free

• Everything will be studied in RCT (Belimumab, Abltacept, Laquinamod, etc.)



IMPORTANT MESSAGES

•Under treatment leads to renal failure, dialysis, transplantation

•Over treatment kills patients from complications

•Vigorous treatment only safe with a vigilant M.D.

• Geral B Appel, M.D

Pathogenesis Clinical Manifestation Pathological ... · Nephrology Board Review 19 /0757 Thaweepong...

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