Nephrology Board Review 19 July 2014 Thaweepong Pajareya M.D. Director, Department of Pathology, Bhumibol Adulyadej Hospital Pathogenesis Clinical Manifestation Pathological Classification Therapeutic options TOPIC Thaweepong Pajareya M.D. 1
CAUSES OF DEATH IN SLE 1950 1955 1956 1962 1963 1973 1973 1987 1978-2008 Patients 491 491 491 389 500 All deaths (%) Death from nephritis (%) Death from infections (%) 12 20 19 22 15 26 36 14 4 8 16 12 18 39 25 Rahman A et al. In Lupus Nephritis, second edition. 2011. 35 58. Thaweepong Pajareya M.D. 2
PATHOGENIC AUTOANTIBODIES IN SLE Antigen specificity Prevalence (%) Anti dsdna 70 80 Nucleosomes 60-90 Sm 10 30 α - Actinin 20 C1q 40-50 Rahman A et al. N Engl J Med. 2008;358:929 39. NUCLEOSOMES Thaweepong Pajareya M.D. 3
INDUCTION OF SURFACE BLEB DURING APOPTOSIS Autoimmune 2012 Thaweepong Pajareya M.D. 4
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 Thaweepong Pajareya M.D. 5
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% Thaweepong Pajareya M.D. 6
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 RENAL INVOLVEMENT IN SLE 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 Thaweepong Pajareya M.D. 7
RENAL INVOLVEMENT IN SLE 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 Thaweepong Pajareya M.D. 8
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 Thaweepong Pajareya M.D. 9
RISK FACTORS FOR ESRD Demographic characteristics Male gender Black race Age < 24 Low socioeconomic status Berden JHM: Lupus nephritis, KI 1997,52:538-558 RISK FACTORS FOR ESRD Treatment characteristics No normalization of elevated creatinine Treatment with prednisolone only Histologic characteristics WHO Class IV * Activity index > 12 Chronicity index > 3 Berden JHM: Lupus nephritis, KI 1997,52:538-558 Thaweepong Pajareya M.D. 10
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 Thaweepong Pajareya M.D. 11
Class II Mesangial proliferative LN Class III Focal LN Thaweepong Pajareya M.D. 12
Class IV Diffuse LN Thaweepong Pajareya M.D. 13
Class IV-G Diffuse Global LN Thaweepong Pajareya M.D. 14
Class V Membranous Lupus Thaweepong Pajareya M.D. 15
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 IV. Diffuse lupus nephritis V. Membranous 20 % 50 % 67 % 25 33 % 10 25 % 85 90 % 50 % 75 % > 95 % 50 % > 50 % 60 90 % 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 Thaweepong Pajareya M.D. 16
Mild Proteinuria < 1 gm/24 hr Inactive urinary sediment APPROACH Serum creatinine < 1.2 mg/dl (egfr > 60 ml/min) Normotension Most likely Class I or II Treat extrarenal, follow up Severe Proteinuria > 1 gm/24 hr APPROACH 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 Thaweepong Pajareya M.D. 17
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 ข อบ งช ในการตรวจช นเน อไต เพ อย นย นการว น จฉ ยโรคในรายท ม ภาวะไตอ กเสบและสงส ยเป น โรคล ป ส แต ม เกณฑ การว น จฉ ยโรคล ป สไม ครบตาม ACR criteria เพ อวางแผนร กษาในรายท ม โปรต นในป สสาวะมากกว า 1 กร มต อว น เพ อวางแผนร กษาในรายท ม active nephritic urine sediment [เพ อวางแผนร กษา ในรายท ตรวจพบม proteinuria > 0.5 กร ม/ว น ร วมก บม nephritic urine sediment (RBC > 5/HPF หร อ RBC cast)] เพ อวางแผนร กษาในรายท ตรวจพบการท างานของไตผ ดปกต แบบ เฉ ยบพล นท ไม ทราบสาเหต (ร าง) คาแนะน าในเวชปฏ บ ต สาหร บการด แลร กษาผ ป วยโรคไตอ กเสบล ป สในประเทศไทย สมาคมโรคไตแห งประเทศไทย 2557 Thaweepong Pajareya M.D. 18
ข อบ งช ในการตรวจช นเน อไต เพ อวางแผนร กษาในรายท ได ร บ prednisolone มากกว า 8 ส ปดาห แล วย งไม ตอบสนองต อการ ร กษา (ไม เข าส complete response) เพ อวางแผนร กษาในรายท ได ร บการร กษาแล วแต ย งม การท างานของไตผ ดปกต เพ อแยกระหว าง พยาธ สภาพท ย งอย ในระยะเฉ ยบพล น (active) ก บรอยโรคเก าในการอ กเสบเร อร ง (scar) (ร าง) คาแนะน าในเวชปฏ บ ต สาหร บการด แลร กษาผ ป วยโรคไตอ กเสบล ป สในประเทศไทย สมาคมโรคไตแห งประเทศไทย 2557 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 Thaweepong Pajareya M.D. 19
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 IV LUPUS 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) Thaweepong Pajareya M.D. 20
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 Thaweepong Pajareya M.D. 21
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. NIH STUDY Steinberg AD, Steinberg SC. Arthritis Rheum 1991; 34: 945-950. Thaweepong Pajareya M.D. 22
NIH REGIMEN TREATMENT 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/m 2 /d for 3 days followed by 1 g/m 2 /monthly for 6 to 24 months Pulse cyclophosphamide 0.5 1 g/m 2 monthly for 6 months then quarterly for one year beyond remission Austin HA, Balow JE. Semin Nephrol, No 1, 1999: 2 11 Remission rate 60 70 % DOWNSIDE IVCY Toxicity : Herpes zoster 25%, severe infection 26%, ovarian failure 52%, avascular necrosis Thaweepong Pajareya M.D. 23
More efficient Less toxicity NEWER THERAPY 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 wks after IVCY Follow 41 months Houssiau et al. Arthritis & Rheumatism 46: 2121 2131, 2002. Thaweepong Pajareya M.D. 24
PROBABILITY OF REMISSION LD HD Houssiau et al. Arthritis & Rheumatism 46: 2121 2131, 2002. FREE OF RENAL FLARE LD HD Houssiau et al. Arthritis & Rheumatism 46: 2121 2131, 2002. Thaweepong Pajareya M.D. 25
FREE OF SEVERE INFECTION LD HD Houssiau et al. Arthritis & Rheumatism 46: 2121 2131, 2002. 10 YEARS FOLLOW UP (ELNT) PATIENT SURVIVAL Houssiau FA et al. Ann Rheum Dis;69: 61 64. 2010 Thaweepong Pajareya M.D. 26
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 Thaweepong Pajareya M.D. 27
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 Thaweepong Pajareya M.D. 28
RCT, 42 patients Inclusion criteria SLE criteria by ARA MMF FOR INDUCTION TREATMENT 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 Thaweepong Pajareya M.D. 29
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 Thaweepong Pajareya M.D. 30
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. Partial remiss. No remission 22.5 % 5.8 % 0.005 29.5 % 24.6 % 0.51 47.9 % 69.6 % 0.01 Thaweepong Pajareya M.D. 31
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. Thaweepong Pajareya M.D. 32
MMF VS IVCY FOR INDUCTION ASPREVA LUPUS MANAGEMENT STUDY GROUP (ALMS) International randomized controlled trial 370 LN class III, IV, V 185 IVCY (0.5 1 g/m 2 ) 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 No different between MMF and IVCY in induction Rx Apple GB, Contreras G, Dooley MA et al. J Am Soc Nephrol 2009;20:1103 12. Thaweepong Pajareya M.D. 33
TREATMENT OF LUPUS 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) KDIGO guideline for lupus nephritis. Kidney Int. 2012 MAINTENANCE TREATMENT FOR PROLIFERATIVE LN Thaweepong Pajareya M.D. 34
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/m 2 ) 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 Contreras G, et al, N Engl J Med; 350, 971 80. 2004 Thaweepong Pajareya M.D. 35
PATIENT SURVIVAL AZA MMF IVCY Contreras G, et al, N Engl J Med; 350, 971 80. 2004 EVENT-FREE SURVIVAL MMF AZA IVCY Contreras G, et al, N Engl J Med; 350, 971 80. 2004 Thaweepong Pajareya M.D. 36
RELAPSE FREE SURVIVAL IVCY MMF AZA Contreras G, et al, N Engl J Med; 350, 971 80. 2004 SIDE EFFECTS Hosp D/pt yr (%) Amenorrhea (%) Infection (%) Major (%) Maintenance MMF and AZA IVCY 13 associated 32 with 68 significant less hospital 12 AZA days, amenorrhea and 1* 7.5* 28* infections than IVCY 3 MMF 1* 6.1* 21* 3 Contreras G, et al, N Engl J Med; 350, 971 80. 2004 Thaweepong Pajareya M.D. 37
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 MMF AZA Houssiau FA et al. Ann Rheum Dis ; 69:2083 2089. 2010 Thaweepong Pajareya M.D. 38
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 Dooley MA, et al. N Engl J Med 2011;365:1886-95. Thaweepong Pajareya M.D. 39
RENAL FLARE MMF AZA P = 0.03 Dooley MA, et al. N Engl J Med 2011;365:1886-95. 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) KDIGO guideline for lupus nephritis. Kidney Int. 2012 Thaweepong Pajareya M.D. 40
RECOMMENDATION SEVERE LUPUS NEPHRITIS RPGN or multiorgan: NIH Others MMF induction Euro Lupus NIH induction Maintenance MMF or AZA TREATMENT OF CLASS V LUPUS NEPHRITIS Thaweepong Pajareya M.D. 41
TREATMENT OF LN CLASS V PRED VS IVCY VS CYA 42 LMN, NS Pred AD Pred + IVCY AM x 6 Pred + CyA CyA : relapse Austin HA et al. J Am Soc Nephrol. 20:901-911. 2009 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 Thaweepong Pajareya M.D. 42
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) Thaweepong Pajareya M.D. 43
ข อบ งช ในการส งปร กษา อาย รแพทย โรคไต ย นย นการว น จฉ ยโรคไตอ กเสบล ป ส ในกรณ ท ม ข อ สงส ย ประเม นความร นแรงของโรคไตอ กเสบล ป ส วางแผนร กษาโรคไตอ กเสบล ป ส โดยเฉพาะผ ป วยท ม nephrotic range proteinuria หร อม การท างานของไต ผ ดปกต หร อไม ตอบสนองต อการร กษา ร วมต ดส นใจและวางแผนการร กษาในภาวะพ เศษบาง กรณ ได แก การต งครรภ และการวางแผนผ าต ด เป นต น (ร าง) คาแนะน าในเวชปฏ บ ต สาหร บการด แลร กษาผ ป วยโรคไตอ กเสบล ป สในประเทศไทย สมาคมโรคไตแห งประเทศไทย 2557 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.) Thaweepong Pajareya M.D. 44
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 Thaweepong Pajareya M.D. 45