Lupus nephritis 2016

This is a presentation on Lupus nephritis, based on ACR guideline.

1. lupus nephritis DR. TALHA-SAMI-UL-HAQUE HMO MU-VA DHAKA MEDICAL COLLEGE HOSPITAL

2. In 1941, Klemperer, Pollack and Baehr first described systemic lupus erythematosus (SLE) as one of the Connective Tissue Disease.

3. systemic lupus erythematosus Systemic lupus erythematosus is an autoimmune disease in which organs and cells undergo damage initially mediated by tissue binding autoantibodies and immune complexes.

4. Lupus nephritis Lupus nephritis is histologically evident in most patients with SLE. One of the most serious manifestations of   SLE. Usually arises within 5 years of diagnosis.

5. Pathophysiology Autoimmunity plays a major role in the pathogenesis of lupus nephritis .

6. The characteristics of the nephritogenic autoantibodies associated with lupus nephritis are as follows   : Antigen specificity directed against nucleosome or double-stranded DNA ( dsDNA ) - Some anti- dsDNA antibodies cross-react with the glomerular basement membrane. Higher-affinity autoantibodies may form intravascular immune complexes, which are deposited in glomeruli. Cationic autoantibodies have a higher affinity for the anionic glomerular basement membrane. Autoantibodies of certain isotypes (immunoglobulin IgG   1  and IgG   3 ) readily activate complement.

7. Autoantibodies Form pathogenic immune complexes intravascularly Immune complexes deposited in glomeruli Bind to antigens already located in the glomerular basement membrane Immune complexes in situ Activating complement and attracting inflammatory cells, including lymphocytes, macrophages, and neutrophils Promote an inflammatory response The histologic type of lupus nephritis that develops depends on numerous factors, including the antigen specificity and other properties of the autoantibodies and the type of inflammatory response that is determined by other host factors .

8. Etiology There are multiple susceptibility factors, which result in abnormal immune responses , which vary among different patients. These factors include: Genetic factors Immunologic factors Environmental factors

9. Genetic factors Genetic predisposition plays an important role in the development of both SLE and lupus nephritis. Multiple genes, many of which are not yet identified, mediate this genetic predisposition [ Human leukocyte antigen (HLA) class II genes, Complement genes, FcγR genes and others]

10. Human leukocyte antigen (HLA) class II genes include the following: HLA-DR2  and  HLA-DR3  are associated with SLE HLA-DR4  is associated with a lower prevalence of SLE and appears to be protective Complement genes include the following: C1Q, C1R,  and  C1S  deficiencies are associated with SLE, lupus nephritis, and production of anti- dsDNA C2  and  C4  deficiencies are associated with SLE or lupuslike syndrome C4A  and  C4B  (possibly) gene deletions are associated with SLE

11. FcγR genes include the following: These mediate the binding of IgG and IgG -containing immune complexes to cells such as macrophages and other mononuclear phagocytes FcγRIIa binds to IgG   2  and is encoded by 2 codominant alleles, H131 (or high affinity) and R131 (or low affinity); the low-affinity phenotype (homozygous for R131 allele; 131R/R) is associated with lupus nephritis in African Americans FcγRIIIa binds to IgG   1  and is encoded by 2 codominant alleles, V158 (or high affinity) and F158 (or low affinity); the low-affinity phenotype (homozygous for F158 allele; 158F/F) is associated with SLE Other relevant genes include the following: Cytokine genes - Certain polymorphisms of the  IL10  gene (high producers) and possibly the  IL1RN  and  TNFA  genes (low producers) are associated with SLE Mannose-binding lectin genes - These gene polymorphisms are associated with an increased risk of SLE Apoptosis genes - Defects of several apoptosis genes are associated with lupuslike syndromes in mice and, rarely, SLE in humans, including  CD95 (Fas) and  CD178  ( FasL )

12. Immunologic factors Patients with SLE have poor clearance mechanisms for cellular debris . Nuclear debris from apoptotic cells induces plasmacytoid dendritic cells to produce interferon- α, which is a potent inducer of the immune system and autoimmunity. Autoreactive B lymphocytes , which are normally inactive, become active in SLE because of a malfunction of normal homeostatic mechanisms, resulting in escape from tolerance. This leads to the production of autoantibodies.  Anti- dsDNA antibodies , develop through a process of epitope spreading.

13. Environmental Factor UV light EBV Smoking Alcohol Silica dust

14. Epidemiology

15. 9 1 20-40

16. Bangladesh

17. Clinical features: Symptoms Asymptomatic Symptoms of active systemic lupus erythematosus (SLE), including fatigue, fever, rash, arthritis, serositis , or central nervous system (CNS) disease . Symptoms related to active nephritis may include peripheral edema secondary to hypertension or hypoalbuminemia . Other symptoms directly related to hypertension that are commonly associated with diffuse lupus nephritis include headache, dizziness, visual disturbances, and signs of cardiac decompensation .

18. Focal and diffuse lupus nephritis : evidence of generalized active SLE with the presence of a rash, oral or nasal ulcers, synovitis , or serositis . Signs of active nephritis are also common. Active lupus nephritis : hypertension , peripheral edema, and, occasionally, cardiac decompensation . Membranous lupus nephritis : signs of an isolated nephrotic syndrome are common. These include peripheral edema, ascites, and pleural and pericardial effusions without hypertension . Clinical features: Signs

19. Several studies have focused on the discrepancy between clinical presentation and pathologic findings at renal biopsy in patients with SLE. Silent LN has been reported not only in class II but also in class IV. Even patients with low-level proteinuria (<1g/24h) have demonstrated significant renal involvement with proliferative LN (classes III or IV ).

20. Differential Diagnoses Chronic Glomerulonephritis Diffuse Proliferative Glomerulonephritis Granulomatosis with Polyangiitis (Wegener Granulomatosis ) Membranous Glomerulonephritis Polyarteritis Nodosa Rapidly Progressive Glomerulonephritis

21. Investi gations

22. Investigations:

23. Laboratory tests Blood urea nitrogen (BUN ) Serum creatinine Urine R/M/E (to check for protein, red blood cells [RBCs], and cellular casts) A spot urine test for creatinine and protein concentration (normal creatinine excretion is 1000 mg/24 h/1.75 m  2 ; normal protein excretion is 150-200 mg/24 h/1.75 m  2 ; normal urinary protein-to-creatinine ratio is <0.2) A 24-hour urine test for creatinine clearance and protein excretion

24. ANA [for diagnosis SLE] Antibodies to double-stranded DNA ( dsDNA ), ↑ Complement (C3, C4, and  CH 50 ), ↓ Erythrocyte sedimentation rate (ESR ), ↑ C-reactive protein (CRP) levels . ↔ Anti-C1q antibodies ↑ [less sensitive then Anti dsDNA , but more specific] Laboratory tests

25. Urinary biomarkers can accurately identify active lupus nephritis in children : Alpha-1-acid glycoprotein (AGP) Ceruloplasmin Lipocalin -like prostaglandin D synthase (LPGDS) Transferrin Laboratory tests

26. Features % Proteinuria 100 Miroscopic hematuria 80 Tubular abnormalities 60-80 Reduced renal function 40-80 Nephrotic syndrome 45-65 Granular casts 30 Rapidly declining renal function 30 Hypertension 15-50 Hyperkalemia 15 Macroscopic hematuria 1-2 Acute renal failure 1-2

27. ACR criteria ACR criteria Persistent proteinuria >0.5 gm per day or greater than 3+ by dipstick, and/or Cellular casts including red blood cells [RBCs], hemoglobin, granular, tubular, or mixed Review of the ACR criteria Spot urine protein/creatinine ratio of >0.5 Active urinary sediment (>5 RBCs/HPF, >5 WBCs/HPF in the absence of infection, or cellular casts limited to RBC or WBC casts

28. Renal biopsy All patients with clinical evidence of active LN, previously untreated, undergo renal biopsy (unless strongly contraindicated ) for Classified by current ISN/RPS classification Disease evaluated for activity and chronicity Identify additional or alternative causes of renal disease Determining prognosis and treatment

29. Indications for renal biopsy in patients with systemic lupus erythematosus Increasing serum creatinine without compelling alternative causes (such as sepsis, hypovolemia , or medication) Confirmed proteinuria of 1.0 gm per 24 hours (either 24-hour urine specimens or spot protein/creatinine ratios are acceptable ) Combinations of the following, assuming the findings are confirmed in at least 2 tests done within a short period of time and in the absence of alternative causes: Proteinuria 0.5 gm per 24 hours plus hematuria , defined as 5 RBCs per hpf Proteinuria 0.5 gm per 24 hours plus cellular casts

30. International Society of Nephrology/Renal Pathology Society 2003 classification of LN Class I Minimal mesangial LN Class II Mesangial proliferative LN Class III Focal LN (50% of glomeruli) III (A): active lesions III (A/C): active and chronic lesions III (C): chronic lesions Class IV Diffuse LN (50% glomeruli) Diffuse segmental (IV-S) or global (IV-G) LN IV (A): active lesions IV (A/C): active and chronic lesions IV (C): chronic lesions Class V Membranous LN Class VI Advanced sclerosing LN (90% globally sclerosed glomeruli without residual activity)

31. Class I Delicate mesangial positivity for IgG . No structural changes by light microscopy

32. Class iI Mesangial cell proliferation, mesangial matrix expansion. Granular mesangial positivity of all three immunoglobulins and both complements (C1q and C3) (“ full house” pattern )

33. Class iiI Less than 50% of all glomeruli, segmental or global, swelling and proliferation of endothelial and mesangial cells associated with leukocyte accumulation, capillary necrosis, and hyaline thrombi; extracapillary proliferation, crescents. Full house pattern as in class II, immune deposits also identified in tubular basement membranes, interstitial capillary walls, interstitial collagen, arterial intima, and media, Fibrinogen positivity

34. Class IV Lesions similar to Class III, but involves > 50% of glomeruli

35. Wire loop lesions

36. Hyaline thrombi

37. Class V Diffuse thickening of the capillary walls due to deposition of subepithelial immune complexes, increased production of basement membrane-like material There are delicate subepithelial immune deposits staining for IgG with or without mesangial deposits

38. Class VI Sclerosis of more than 90% of the glomeruli, end stage renal disease, severe tubular atrophy, interstitial fibrosis, inflammation.

39. treat ment

40. treatment The principal goal of therapy in lupus nephritis is to normalize renal function or, at least, to prevent the progressive loss of renal function . Therapy differs depending on the pathologic lesion .   It is important to treat extrarenal manifestations and other variables that may affect the kidneys . Adjunctive Treatments Primary disease management by immunosuppressive agents Induction Therapy Maintenance Therapy Lifestyle Changes

41. Adjunctive Treatments Drugs Cause Hydroxychloroquine [Max 6–6.5 mg/kg body weight] All SLE patients with; unless there is a contraindication: Lower rates of Flare Reduced renal damage Less clotting events ACEi /ARBs Patients with proteinuria >0.5 gm /day Reduces proteinuria by 30%, and Significantly delays doubling of serum creatinine Delays progression to ESRD Antihypertensive Target of ≤130/80 mmHg Significant delay in progression of renal disease Statin therapy Patients with LDL >100 mg/dl As GFR<60ml/min/1.73m 2 & SLE itself accelerated atherosclerosis Calcium supplementation Prevent osteoporosis if the patient is on long-term corticosteroid therapy

42. immunosuppressive agents Depends upon class of LN diagnosed on kidney biopsy along with presence of extra-renal manifestations of SLE Goals of immunosuppressive treatment: Long-term preservation of renal function, Prevention of flares, Avoidance of treatment-related harms, and Improved quality of life and survival.

43. Class I LN (minimal- mesangial LN) Treatment as dictated by the extrarenal clinical manifestations of lupus Class I LN has no clinical kidney manifestations. Class I LN is not associated with long-term impairment of kidney function

44. May require treatment if proteinuria is greater than 1000 mg/day. Consider prednisone in low-to-moderate doses ( ie , 20-40 mg/day) for 1-3 months, with subsequent taper. Class II LN ( mesangial -proliferative LN)

45. Class III LN ( focal) and class IV LN ( diffuse) At high risk of progressing to ESRD Require aggressive therapy . Therapy for class III and IV LN has 2 phases: Initial/Induction phase: to rapidly decrease kidney inflammation Maintenance phase: to consolidate treatment over a longer time.

46. Initial/Induction THERAPY

47. Initial/Induction phase Initial therapy with corticosteroids , combined with either cyclophosphamide or MMF. 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.

48. glucocorticoids Pulse IV glucocorticoids ( 500–1000 mg methylprednisolone daily for 3 doses) in combination with immunosuppressive therapy is recommended. Followed by daily oral glucocorticoids (0.5–1 mg/kg/day ), followed by a taper to the minimal amount necessary to control disease.

49. Regimens for initial therapy in class III/class IV LN [International society of nephrology- kidney disease improving global outcome]

50. MMF CYC Non Asian = 3gm/D Asian = 2 gm /D Class III/IV + crescents = 3gm/D Proteinuria + recent significant rise in creatinine = 3gm/D In severe class III/IV LN In whites, low- and high-dose regimens were equivalent in efficacy. Serious infections were less frequent with the lower doses Low and high-dose regimens similar rates of LN flares, end-stage renal disease, and doubling of the serum creatinine.

51. Important considerations for CYC The use of sodium-2-mercaptoethane ( mesna ) will also minimize the risk of hemorrhagic cystitis when cyclophosphamide is given as i.v. pulses. Lifetime maximum of 36 g cyclophosphamide in patients with systemic lupus as there is chance of hematologic malignancies later in life . The dose of cyclophosphamide should be decreased by 20 % ( CrCl 25-50ml/min ) or 30% (10–25 ml/min ) To minimize bladder toxicity with oral cyclophosphamide, suggest instructing patients to take cyclophosphamide in the morning, and to drink extra fluid. To protect fertility, women should be offered prophylaxis with leuprolide and men testosterone. Ovarian tissue cryopreservation/sperm banking are other options.

52. How can we predict outcome?? After 8 week: ≥ 25% reduction in proteinuria and/or normalization of C3 and/or C4 serum levels = likely to show good clinical renal responses After 6 months: decrease in serum creatinine and in proteinuria to <1 gm /D predicts a good long-term outcome

53. Definitions of response to therapy Complete response : Return of SCr to previous baseline, plus a decline in the uPCR to <500 mg/g (<50 mg/ mmol ). Partial response : Stabilization (±25%), or improvement of SCr , but not to normal , plus a ≥50 % decrease in uPCR . If there was nephrotic -range proteinuria ( uPCR≥3000 mg/g [≥300 mg/ mmol ]), improvement requires a ≥50 % reduction in uPCR , and a uPCR <3000 mg/g [<300 mg/ mmol ]. Deterioration : There is no definition of deterioration in LN to define treatment failure. A sustained 25% increase in SCr is widely used but has not been validated.

54. If the patient not improved?? Switch REGIMEN

55. Other Initial Regimens Regimens Rituximab When treatment failed with MMF/CYC Azathioprine 2 nd line protocol Less effective than CYC MPA Less nausea & diarrhea than MMF Should measured 1 hour after a dose Cyclosporine (4–5 mg/ kg/d) was used for 9 months, and then tapered over the next 9 months. No differences in responses, relapse rate, Infections and leukopenia with CYC. ACR guideline preferred it for maintenance therapy. Tacrolimus Equivalent to high-dose IV CYC in inducing complete and partial remissions of LN

56. maintenance therapy

57. Azathioprine (1.5–2.5 mg/kg/d) or MMF (1–2 g/d in divided doses ) ± Low-dose oral corticosteroids Calcineurin inhibitor s with low-dose corticosteroids be used for maintenance therapy in patients who are intolerant of MMF and azathioprine . maintenance therapy

58. Complete remission is achieved Repeat kidney biopsy Change in therapy Continued for at least 1 year Consideration for tapering Kidney function deteriorates and/or proteinuria worsens Treatment be increased to the previous level of immunosuppression that controlled the LN YES NO After 1 year

59. Duration of Therapy There is no evidence to help determine the duration of maintenance therapy. The average duration of immunosuppression was 3.5 years in seven RCTs. Immunosuppressive therapy should usually be slowly tapered after patients have been in complete remission for a year.

60. Class V LN (membranous LN) Generally treated with prednisone for 1-3 months, followed by tapering for 1-2 years if a response occurs. If no response occurs, the drug is discontinued . Immunosuppressive drugs are generally not used unless renal function worsens or a proliferative component is present on renal biopsy samples. 

61. Class VI LN (advanced sclerosis LN) Treated with corticosteroids and immunosuppressives only as dictated by the extrarenal manifestations of systemic lupus . Dialysis and Kidney transplantation

62. Lifestyle Changes for Lupus Nephritis Drink enough fluids to stay well hydrated. Eat a low-sodium diet, especially if hypertension is an issue. Avoid smoking and drinking alcohol. Exercise regularly. Maintain a healthy blood pressure. Limit cholesterol. Avoid medications that can affect the kidneys, such as nonsteroidal anti-inflammatory drugs (NSAIDs).

63. Relapse of LN Treated with the initial therapy followed by the maintenance therapy that was effective in inducing the original remission Consider a repeat kidney biopsy during relapse if there is suspicion that the histologic class of LN has changed, or there is uncertainty whether a rising SCr and/or worsening proteinuria represents disease activity or chronicity.

64. Systemic lupus and thrombotic microangiopathy Antiphospholipid syndrome occurs when immune system mistakenly attacks some of the normal proteins in blood .  The antiphospholipid anti-body syndrome (APS) involving the kidney in systemic lupus patients, with or without LN.

65. Blood tests for antiphospholipid syndrome look for at least one of the following three antibodies in your blood: Lupus anticoagulant Anti- cardiolipin Beta-2 glycoprotein I To confirm a diagnosis of antiphospholipid syndrome, the antibodies must appear in your blood at least twice, in tests conducted at least 12 weeks apart. Systemic lupus and thrombotic microangiopathy

66. Heparin:  Typically, first be given as injection, combined with another blood thinner in pill form, likely warfarin (Coumadin). Warfarin:  After several days of combined heparin and warfarin, discontinue the heparin and continue the warfarin, possibly for the rest of life . Aspirin:  In some cases, may recommend adding low-dose aspirin to treatment plan . Target INR 2–3 Systemic lupus and thrombotic microangiopathy

67. Patients with systemic lupus and thrombotic thrombocytopenic purpura (TTP) receive plasma exchange as for patients with TTP without systemic lupus. Systemic lupus and thrombotic microangiopathy

68. Pathological classification of vascular lesion in lupus nephritis Uncomplicated vascular immune complex deposits Noninflammatory necrotic vasculopathy Thrombotic microangiopathy True vasculitis

69. Uncomplicated vascular immune complex deposits On light microscopy, the extraglomerular arteries and arterioles with immune complex deposition usually normal. No thrombosis, necrosis, inflammatory infiltration of the blood vessel wall. On immunofluorescence microscopy, the deposits may contain IgG , IgA, IgM and various compliment components.

70. Noninflammatory necrotic vasculopathy On light microscopy, smudgy eosinophilic , fuchsinophilic material that stains focally positive for fibrin is seen to occupy the lumen and intima of arteries and arterioles. Endothelium is usually swollen or denuded. No inflammatory infiltrate. On immunofluorescence microscopy, IgG , IgA, IgM and various compliment components.

71. Thrombotic microangiopathy Marked luminal narrowing or total occlusion by intraluminal, subendothelial , or medial accumulation of eosinophilic material with endothelial swelling, denudation and sometime fragmented and hemolyzed erythrocytes. Absence of discrete immune deposite .

72. True vasculitis Prominent inflammatory cell infiltration of the arterial wall by neutrophils and mononuclear leukocytes can be seen. Fibrinoid necrosis, usually most severe in the intime Rupture of elastic lamellae. Less intense staining for immunoglobulin and compliment fractions.

73. Systemic lupus and pregnancy Women be counseled to delay pregnancy until a complete remission of LN has been achieved . In patients with prior LN but no current evidence of systemic or renal disease activity: no nephritis medications are necessary Patients with mild systemic activity : may be treated with HCQ Clinically active nephritis is present, or there is substantial extrarenal disease activity : glucocorticoids ( at doses necessary to control disease activity) ± AZA

74. If pregnant patients are receiving corticosteroids or azathioprine, we suggest that these drugs not be tapered during pregnancy or for at least 3 months after delivery . Contraindicated : High-dose glucocorticoid [hypertension and diabetes mellitus]. MMF, CYC, and methotrexate should be avoided because they are teratogenic . Class III or IV with crescents : consideration of delivery after 28 weeks for a viable fetus. Administration of low-dose aspirin during pregnancy to decrease the risk of fetal loss. Systemic lupus and pregnancy

75. Monitoring Activity of LN

76. Prognosis