Lupus Nephritis


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SNS 3rd Conference Khartoum Sudan 2009

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Lupus Nephritis

  1. 1. Khartoum-Sudan 24 th of january 2009 LUPUS NEPHRITIS PROF.BABIKIR KABALLO MBBS,MD(U of K),FRCP(LONDON) The 3 rd congress of the sudanese society of kidney disease and transplantation in collaboration with the Sudan-PD
  2. 5. <ul><li>Systemic lupus erythematosus ( SLE ) is the prototype of complex autoimmune diseases and is characterized by extreme </li></ul><ul><li>breakdown of self-tolerance which results in a wide range of immunologic abnormalities and immune complex formation. </li></ul>
  3. 6. Current model for development of autoimmune diseases <ul><li>Activation of T cells, B cells dendritic cells. </li></ul><ul><li>Impaired clearance of apoptotic material. </li></ul><ul><li>Overactive T–B cell interactions. </li></ul><ul><li>Molecular mimicry. </li></ul><ul><li>Chimerism </li></ul><ul><li>Faulty selection. </li></ul>
  4. 7. <ul><li>It is thought to develop when genetically predisposed individuals are exposed to one or more environmental triggers </li></ul>
  5. 8. Candidate environmental triggers <ul><li>cigarette smoking . </li></ul><ul><li>endogenous viruses or viral-like elements. </li></ul><ul><li>crystalline silica. </li></ul><ul><li>ultraviolet light . </li></ul><ul><li>demethylating drugs. </li></ul><ul><li>exogenous hormoneuse . </li></ul>
  6. 9. <ul><li>These exposures </li></ul><ul><li>may interact with multiple genetic factors in determining susceptibility to SLE. </li></ul>
  7. 10. current model for the development of autoimmune diseases <ul><li>Genome scans on families have revealed several putative regions linked to the disease that includes: cytokine genes . </li></ul><ul><li>lymphocyte surface and molecular signaling genes. </li></ul><ul><li>interacting with a variety of potential environmental exposures. </li></ul>
  8. 11. Antigens must be processed in order to be recognised by T cells T cell response No T cell response No T cell response No T cell response No T cell response ANTIGEN PROCESSING Cell surface peptides of Ag Y T Soluble native Ag Cell surface native Ag Soluble peptides of Ag Cell surface peptides of Ag presented by cells that express MHC antigens
  9. 12. IL-2 Thomas F. Lint, Ph.D. Rush Medical College TCR CD3 CD28 CD4 T H 0 Cell MHC II CD40 M  IL-2 R Cell Division CD40L B7 IFN  IL-1 IL-6 TNF 
  10. 13. <ul><li>However, most studies agree that SLE patients have elevated IL-10 and IL-6 levels, two cytokines that are known to play an important role in the pathogenesis of SLE </li></ul>
  11. 14. <ul><li>Impaired clearance of apoptotic or </li></ul><ul><li>necrotic debris, as might occur with rare </li></ul><ul><li>deficiencies of complement components , </li></ul><ul><li>can provide sufficient self-antigen for </li></ul><ul><li>effective presentation to T cells. </li></ul>
  12. 15. <ul><li>________________________ </li></ul><ul><li>Mary K. Crow,Collaboration, N Engl j med 358;9 february 28, 2008 </li></ul>
  13. 16. <ul><li>________________________ </li></ul><ul><li>Mary K. Crow,Collaboration, N Engl j med 358;9 february 28, 2008 </li></ul>
  14. 17. <ul><li>The lack of consistency between studies is </li></ul><ul><li>frustrating . </li></ul><ul><li>SLE is a heterogeneous disorder, exemplified by the ACR criteria which require only 4. </li></ul><ul><li>different genes are linked to the development of different SLE endophenotypes. </li></ul>
  15. 18. Racial background and global distribution <ul><li>CaucasianAmericans, Canadias andSpaniards with incidences of 1.4 , 1.6 and 2.2 cases per 100,000 people respectively. France </li></ul><ul><li>( 5.0 cases/100,000 ), </li></ul><ul><li>Sweden ( 4.7 cases/100,000 ), </li></ul><ul><li>in Asian ( 10.0 cases/100,000 ) and Afro-Caribbean ( 21.9 cases/100,000 ) residents of the UK. </li></ul><ul><li>________________________ </li></ul><ul><li>Danchenko N, Lupus 2006; 15: 308 – 18 </li></ul>
  16. 19. <ul><li>induction of tolerance to self-antigens. </li></ul><ul><li>prevention of pathogenic effects autoantibody production, </li></ul><ul><li>interference with the cytokine network and signal transduction, </li></ul><ul><li>the identification and treatment of any infectious triggers </li></ul><ul><li>stem cell therapy, </li></ul>Research under way
  17. 20. <ul><li>may present as the sole clinical manifestation of systemic lupus erythematosus </li></ul><ul><li>or, more commonly, as part of multiorgan involvement. </li></ul>Lupus Nephritis
  18. 21. <ul><li>The severity of lupus nephritis varies from mild </li></ul><ul><li>lesions with subclinical disease to diffuse proliferative </li></ul><ul><li>lupus nephritis (DPLN). The latter may </li></ul><ul><li>present with proteinuria, hematuria, and renal </li></ul><ul><li>impairment and may progress to end-stage renal </li></ul><ul><li>disease (ESRD). </li></ul>
  19. 23. <ul><li>Renal biopsy is required for a </li></ul><ul><li>precise diagnosis of lupus nephritis, and in 1982, </li></ul><ul><li>theWorld Health Organization (WHO) classified </li></ul><ul><li>this disease based on histological features into 6 </li></ul><ul><li>categories.1 WHO class I and II lesions have </li></ul><ul><li>good renal prognosis and are not an indication </li></ul><ul><li>for specific therapy. </li></ul>
  20. 24. <ul><li>Proliferative disease (WHO </li></ul><ul><li>classes III, IV, Vc, and Vd) is a more fulminant </li></ul><ul><li>condition and usually requires aggressive treatment </li></ul><ul><li>to induce remission and prevent significant </li></ul><ul><li>renal morbidity and overall mortality. </li></ul>
  21. 25. <ul><li>Diffuse proliferative lupus nephritis [Type1V] is the most common and severe form of lupus nephritis in which renal insufficiency is frequently seen . </li></ul><ul><li>Aggressive therapy is primarily indicated in all patients with type 1V lupus nephritis . </li></ul><ul><li>___ _____________________ </li></ul><ul><li>Schwartz , et al. Am J Kidney Dis 1989;13:273 </li></ul>
  22. 26. <ul><li>WHO class IV lupus nephritis has the worst prognosis without treatment </li></ul><ul><li>5-year renal survival has improved significantly during the last 30 years. </li></ul><ul><li>At present, the majority of treated patients achieve complete or partial renal remission at 12 months and have stable renal function at 10 years. </li></ul><ul><li>Management of DPLN remains controversial </li></ul>
  23. 27. World Health Organization Classification of Lupus Nephritis (Modified) Normal light microscopy findings; abnormal electron microscopy findings Minimal mesangial Class I Hypercellular on light microscopy Mesangial proliferative class II <50% of glomeruli involved Focal proliferative class III >50% of glomeruli involved; classified segmental or global; aggressively treated Diffuse proliferative class IV Predominantly nephrotic disease Membranous class V Chronic lesions and sclerosis Advanced sclerosing Class VI
  24. 36. Clinically useful markers of activity <ul><li>  </li></ul><ul><li>clinical history </li></ul><ul><li>physical examination, </li></ul><ul><li>organ specific functional tests </li></ul>
  25. 37. <ul><li>a rise in IgG anti-double-stranded DNA titers </li></ul><ul><li>a fall in complement levels ( especially CH50, C3 and C4 ) an elevation in complement split products </li></ul><ul><li>an increase in erythrocyte-bound C4d </li></ul><ul><li>low serum levels of complement C1q </li></ul><ul><li>Falling levels of anti-DNA antibodies may occur in association with active disease </li></ul><ul><li>Increases ( ESR ) </li></ul>Clinically useful markers of activity serologic studies:
  26. 38. <ul><li>The optimal treatment of lupus nephritis (LN) is uncertain </li></ul><ul><li>no specific therapy is indicated for class I and II. </li></ul><ul><li>whereas treatment is often indicated for some patients with membranous or mild focal proliferative LN. </li></ul>
  27. 39. THERAPY <ul><li>1) Immunosuppressive therapy </li></ul><ul><li>2)nonimmunosuppressive therapy </li></ul>
  28. 40. <ul><li>Immunosuppressive Therapy </li></ul><ul><li>The goal is to induce immunologic remission of the inflammatory manifestations of lupus, resulting in control of renal, extrarenal, & serologic signs of lupus. </li></ul><ul><li>Criteria for defining a response to therapy: </li></ul><ul><li>1)Renal function(GFR) </li></ul><ul><li>2)Proteinuria (protein : Cr ratio) </li></ul><ul><li>3)Urinary sediment </li></ul>
  29. 41. <ul><li>Nonimmunologic therapy: </li></ul><ul><li>1)aggressive antihypertensive & antiproteinuric therapy with ACEI & ARB. The goal BP is <13080 & protein excretion <500mgday </li></ul><ul><li>2)aggressive lipid lowering with statin therapy. Goal serum LDL cholestrol <80mgdl </li></ul>
  30. 42. <ul><li>Treatment is almost always indicated in </li></ul><ul><li>1.patients with severe membranous LN </li></ul><ul><li>a-with severe nephrotic syndrome and/or rising creatinine, or </li></ul><ul><li>b- associated with focal or diffuse proliferative changes. </li></ul><ul><li>2-severe focal and diffuse proliferative LN. </li></ul>
  31. 43. <ul><li>Immunosuppressive therapy for proliferative LN consists of </li></ul><ul><li>induction and </li></ul><ul><li>maintenance phases: </li></ul>
  32. 44. Goals of induction therapy <ul><li>produce a remission in lupus activity as evidenced by resolution of extrarenal symptoms, </li></ul><ul><li>correction of serologic manifestations </li></ul><ul><li>resolution of hematuria, pyuria, and cellular casts </li></ul><ul><li>reduction or stabilization in the serum creatinine </li></ul>
  33. 45. <ul><li>Pulse glucocorticoids   therapy is initiated with intravenous pulse methylprednisolone (500 to 1000 mg given over 30 minutes for three days) </li></ul><ul><li>cyclophosphamide is not seen for 10 to 14 days. </li></ul><ul><li>monthly methylprednisolone pulses are often given concurrent with monthly intravenous cyclophosphamide for six months </li></ul>Illei, GG, Austin, HA, Crane, M, et al. Ann Intern Med 2001; 135:248.
  34. 46. <ul><li>the probability of avoiding renal failure at 10 to 12 years among survivors was [ 4 ]: </li></ul><ul><li>90 percent with cyclophosphamide </li></ul><ul><li>60 percent with azathioprine </li></ul><ul><li>20 percent with prednisone alone </li></ul>
  35. 47. <ul><li>The median MMF dose received was 1500 mg/day during the first 12 months. Subsequently, the median MMF dose </li></ul><ul><li>received decreased during maintenance. </li></ul><ul><li>Maintenance MMF was titrated to gastrointestinal side effects and </li></ul><ul><li>leukopenia, and decreased in patients who had sustained </li></ul><ul><li>remission after a minimum of 12 months of therapy. </li></ul>
  36. 48. <ul><li>one trial comparing mycophenolate to azathioprine for maintenance therapy, the median mycophenolate dose in the first year was 1500 mg/day and gradually was reduced to 500 to 1000 mg in the third year The median dose for azathioprine was 1.0 to 1.2 mg/kg per day for the duration of the study. </li></ul>Contreras, G, Pardo, V, Leclercq, B, et al. N Engl J Med 2004; 350:971.
  37. 49. <ul><li>The amount of steroids used during maintenanc was determined by relapses. </li></ul>
  38. 50. Clinical manifestations and serological testing of SLE in the target population (n=87) Percentages Numbers of patients Criteria 73.6% 64 Malar rash 32.2% 28 Photosensitivity 54% 47 Oral ulcer 2.3% 2 Discoid lupus 95.4% 83 Arthritis/Arthralgia 37.9% 33 Hematological 13.9% 12 Neuropsychiatric 63.2% 55 Renal involvement 37.9% 33 Serositis 96.6% 84 Positive ANA 51.1% 45 Positive antidsDNA
  39. 51. <ul><li>Most physicians rely on diagnostic criteria for lupus that were developed by the American College of Rheumatology or ACR). The diagnosis is made if four or more of the manifestations are present, either serially or simultaneously, during any interval of observations. </li></ul><ul><li>Milder symptoms can be managed with nonsteroidal anti-inflammatory drugs and antimalarial agents. </li></ul>
  40. 52. <ul><li>Renal disease ( especially diffuse proliferative glomerulonephritis ) </li></ul><ul><li>Hypertension </li></ul><ul><li>Male sex </li></ul><ul><li>Young age, older age at presentation </li></ul><ul><li>Poor socioeconomic status </li></ul><ul><li>Black race, which may primarily reflect low socioeconomic status </li></ul><ul><li>Presence of antiphospholipid antibodies </li></ul><ul><li>Antiphospholipid syndrome </li></ul><ul><li>High overall disease activity </li></ul>Poor prognostic factors
  41. 53. <ul><li>Lupus nephritis adds significantly to the morbidity and mortality of patients affected with ( SLE ) </li></ul><ul><li>________________________ </li></ul><ul><li>Appel GB,et al Am J Med 1987; 83: 877 – 885 </li></ul>
  42. 54. <ul><li>Until the middle of the last century, 5 -year survival was < 50% </li></ul><ul><li>________________________ </li></ul><ul><li>Dubois EL, Wallace DJ. Dubois ’ Lupus erythematosus, 3rd edn. Philadelphia, PA: Lea & Febiger, 1987: xii, 775 </li></ul>
  43. 55. <ul><li>In the past 40 years, prognosis for patients with systemic lupus erythematosus ( SLE ) has improved, with 10 -year survival now approximately 90%. </li></ul>
  44. 56. <ul><li>This is due probably to a combination of earlier disease diagnosis and diagnosis of milder disease, due in part to availability of multiple serological tests for SLE , use of steroids and other immunosuppressive agents, and availability of renal dialysis and transplantation </li></ul>
  45. 57. Robert S. Flanc,et al American Journal of Kidney Diseases, Vol 43, No 2 (February), 2004: pp 197-208 <ul><li>Treatment of Diffuse Proliferative Lupus Nephritis: A Meta-Analysis of Randomized Controlled Trials </li></ul>
  46. 59. <ul><li>For the treatment of proliferative lupus nephritis, long-term cyclophosphamide ( CY ) regimens are efficacious, however, at the expense of substantial toxicity </li></ul><ul><li>___ _____________________ </li></ul><ul><li>Austin et al N Engl J Med 1986; 314: 614 – 619 </li></ul>
  47. 60. <ul><li>72-month cumulative probability for remaining free of CRF ranged from 75% to 100% with long-term IVCY therapy. But high incidence of amenorrhea ranging from 29% to 57%. </li></ul><ul><li>___ _____________________ </li></ul><ul><li>Boumpas DT, et al Ann Intern Med 1993; 119: 366 – 369. </li></ul>
  48. 61. <ul><li>NIH group compared a shortterm IVCY ( short-term IVCY ) regimen using six monthly pulses of IVCY to the long-term IVCY using the same six months induction course +12 more pulses of quarterly IVCY maintenance. </li></ul><ul><li>sustained amenorrhea ( 17% versus 64% ) the short-term IVCY group: probability of remaining relapse-free ( 40% versus 87% in longterm IVCY group, P , 0.01 ) </li></ul><ul><li>___ _____________________ </li></ul><ul><li>Donadio JV Jr, et al N Engl JMed 1978; 299: 1151 – 1155 . </li></ul>
  49. 62. <ul><li>In the last decade, sequential regimens of </li></ul><ul><li>short-term CY induction followed by either mycophenolate mofetil ( MMF ) or azathioprine ( AZA ) </li></ul><ul><li>maintenance have shown to be efficacious and safe reducing the long-term exposure to CY </li></ul>
  50. 63. ___ _____________________ G Contreras,et al Lupus 2005; 14; s33
  51. 64. ___ _____________________ G Contreras,et al Lupus 2005; 14; s33
  52. 65. ___ _____________________ G Contreras,et al Lupus 2005; 14; s33
  53. 66. <ul><li>___ _____________________ </li></ul><ul><li>Houssiau FA,et al Arthritis Rheum 2002; 46: 2121–2131 </li></ul>LD CYC,HD CYC+ AZA
  54. 67. ___ _____________________ Houssiau FA,et al Arthritis Rheum 2002; 46: 2121–2131
  55. 68. <ul><li>European induction study </li></ul><ul><li>low dose versus high dose IVCY induction both followed by AZA maintenance remaining free of treatment failure (84% in low dose IVCYand 80% in high dose IVCY; both regimens were associated with low incidence of sustained amenorrhea ( 4% in each group) and severe infections ( 11% in low dose and 22% in high dose IVCY induction). </li></ul><ul><li>___ _____________________ </li></ul><ul><li>Houssiau FA,et al Arthritis Rheum 2002; 46: 2121–2131 </li></ul>
  56. 69. CD4 CD3 Signal 1 mTOR-2 Cytoskeletal stability Survival ? Adhesion molecules Courtesy of prof.barsoum CD154 CD40 1 LFA - ICAM-1 IL - 1 IL - 1r IF - G Calcineurine NFkB CD-52 Other leucocytes
  57. 70. CD4 CD3 Further Lymphocyte Activation CD-52 Other leucocytes Signal 1 Signal 2 Courtesy of prof.barsoum IL - 2 NFATS CD28 B7 CD154 CD40 1 LFA - ICAM-1 G1 G0 IL - 1 IL - 1r IF - G Calcineurine Kinase MAP NFkB Chemokines Cytokines Proteolytic enzymes
  58. 71. G2 G0 M Cyclin D,E/CDK 2 ,4 Cell Cycle - Cip/Kip p27 Growth Proliferation Cyclin B/CDK 1 Cyclin A/CDK 2 Cyclin /CDK CDK 2 Courtesy of prof.barsoum Gap I G1 Mitosis Gap 2 CDK -- Precursors Cyclin Inhibitory Protein Kinase Inhibitory Protein S Synthesis
  59. 72. CD4 P27 CD3 Building The Active Clone Signal 1 Signal 2 Signal 3 CD-52 Other leucocytes NFATS IL - 2r IL - 2 m TOR c - Myc CD28 B7 CD154 CD40 1 LFA - ICAM-1 S G1 G0 G2 Protein Synthesis Translation IL - 1 IL - 1r IF - G M Calcineurine Kinase MAP NFkB IL - 2 Chemokines Cytokines Proteolytic enzymes
  60. 73. CD4 Apoptosis Bcl2 P27 CD3 Activation Interception Strategies- Induction CTLA4 Anti-CD28 CD-52 CAMPATH Pulse Steroids NFATS IL - 2r IL - 2 m TOR c - Myc Caspases CD28 B7 CD154 CD40 1 LFA - ICAM-1 S G1 G0 G2 Protein Synthesis Translation IL - 1 IL - 1r IF - G p53 NO Pro - inflammatory Cytokines M T - reg Calcineurine Kinase MAP NFkB CTLA4 Anti CD40 Basiliximab Daclizumab IL - 2 TGF-  Chemokines Cytokines Proteolytic enzymes
  61. 74. CD4 Apoptosis Bcl2 P27 CD3 Combinations Sequential Immunosuppression PRD Elimination Aza MMF/MPA NFATS IL - 2r IL - 2 m TOR c - Myc Caspases CD28 B7 CD154 CD40 1 LFA - ICAM-1 S G1 G0 G2 Protein Synthesis Translation IL - 1 IL - 1r IF - G CNI PRD p53 NO Pro - inflammatory Cytokines M T - reg Calcineurine Kinase MAP NFkB Anti-Purine TGF- 
  62. 75. SLE in Sudan <ul><li>To the best of our knowledge, clinical features of SLE have not been studied before. However, the incidence of lupus nephritis in the Sudan was reported to be 14.7%. </li></ul>Khalifa I,Kaballo B,Suleiman S,Khalil EA,EI-Hassan AM* Saudi J Kidney DisTransplant2004;15(2):176179
  63. 79. SLE IN SUDAN <ul><li>Kaballo B 1 , Abubakr A 1 , Nur M, Modawi A K 2 , Elnazir EM 3 ,S Ahmed A 3 , A/mageed M 3 , Omer H 3 , H Ibrahem A 3 , Hasan Abu-Aisha 4 </li></ul><ul><li>Nephrology Unit, Military Hospital Omdurman, Sudan </li></ul><ul><li>Juba University, Sudan </li></ul><ul><li>Pathology department, , Military Hospital Omdurman, Sudan </li></ul><ul><li>4. The National Ribat University </li></ul>
  64. 80. <ul><li>Studies of SLE in Arabs are few and virtually there are no studies from North Africa , however lupus in children in Egypt had been studied by Bakr A in 2005 </li></ul>
  65. 83. <ul><li>Renal biopsy was indicated and performed in 50 out of 55 patients with lupus nephritis. Light microscopy and immunofluorescence techniques were used to study biopsies. </li></ul>Methodology
  66. 84. <ul><li>The disease was most frequently seen in mixed tribes ( afro-arabs ) ( 94.3% ) compared to black &quot;Nuba&quot; ( 5.7% ), however, the disease has never been observed in other blacks &quot;Southerners-Nilotics- and Westerners-zagwa and fur tribes- &quot;. </li></ul>Results
  67. 87. Renal involvement among patients (n=55) Percentages Numbers of patients Presentation 31% 17 Reduced urine output 64% 35 Lower limbs oedema/Periorbital oedema 27% 15 Systemic hypertension 62% 34 Hematuria (> 3 RBCs) 62% 34 Active urine sediment 47% 26 Nephrotic syndrome (24 hrs urine protein > 3 grams) 31% 17 S.creatinine > 1.4 mg/dl
  68. 89. <ul><li>Nephritis in general is the most important predictor of poor outcome. Renal manifestations of SLE are variable in clinical presentation and prognosis. Renal involvement is almost invariable, this has been supported by the study of adequate tissue biopsies which showed abnormal histopathology or immune deposits even in the absence of urinary abnormalities. </li></ul>
  69. 91. <ul><li>Also we compared clinical and laboratory manifestations between Arabs and the black one. This revealed serositis and severe features of SLE like neuropsychiatric and renal involvement were common in black than in mixed tribes patients. </li></ul>
  70. 100. <ul><li>We have presented the first review of the clinical mainly criterial characteristics of SLE in Sudan. The clinical pattern is similar to that reported in the literature. </li></ul><ul><li>The major age group to be affected was between 21-30 years. </li></ul><ul><li>SLE patients in Sudan were characterized by the highest incidence of articular manifestations, skin rash, renal involvement, and oral ulcer. </li></ul><ul><li>Our patients had the lowest incidence of thrombocytopenia and neuropsychiatric manifestations. </li></ul>
  71. 101. <ul><li>Although SLE predominantly affects mixed tribes in Sudan, black Africans populations had severe forms of SLE presentation like neuropsychiatric and renal involvement. </li></ul><ul><li>It is quite observable that there is virtual nonexistance of lupus in black Africans in Sudan (westerners {zagwa and fur tribes} and southerners {nilotics}). </li></ul>
  72. 102. PROF. JAN WEENING
  74. 105. ً THANK YOU