• Information
  1. Serological Predictors of Lupus Nephritis
  2. Pathogenesis
  3. World Health Organization Classification of Lupus Nephritis
  4. Presentation
  5. Renal Biopsy and Pathology
  6. Treatment Overview
  7. Cyclophosphamide
  8. Mycophenolate Mofetil
  9. Azathioprine
  10. Dialysis and Transplantation
  11. Experimental Therapy

A. Serological Predictors of Lupus Nephritis [2]

1. Anti-dsDNA Ab - high titer associated with diffuse proliferative glomerulonephritis
2. Anti-Sm Ab - nearly all patients have renal disease
3. Low complement levels - levels drop with disease exacerbation
4. Black female patients at presentation frequently have anti-SSA, -RNP, and -Sm

B. Pathogenesis [3]

1. Nearly all patients with lupus have deposition of immune complexes in their glomeruli
2. Anti-ds DNA Abs often found on basement membrane (subepithelial; formed in situ) [2]
3. IgA and Complement deposition also found membrane
4. Subendothelial immune complexes very common as well
5. Prototypical immune complex and complement mediated renal disease
6. Endothelial cell activation and inflammation (through T lymphocytes) also present

C. World Health Organization Classification of Lupus Nephritis [1]

1. Class I: normal glomeruli (~8% of biopsies)
2. Class II: pure mesangial alterations (~40% of biopsies)
3. Class III: focal glomerulonephritis (~15% of biopsies)
   1. Class IIIA: focal segmental glomerulonephritis (~12% of biopsies)
   2. Class IIIB: focal proliferative glomerulonephritis
4. Class IV: diffuse glomerulonephritis (~25% of biopsies)
5. Class V: diffuse membranous glomerulonephritis (~8% of biopsies)
6. Class VI: advanced sclerosing glomerulonephritis

D. Presentation [4,5,13]

1. Usually asymptomatic at presentation unless nephrotic syndrome develops
   1. These patients present with edema, usually beginning with lower extremities
   2. They also have coagulopathy and hypercholesterolemia
2. Most renal lupus lesions lead to nephrosis (little or no azotemia) - Class II or V
3. However, most renal biopsies are Class III or IV (with poorer prognosis)
4. A small subset of patients have glomerular sclerosis with azotemia, little protein loss
5. Laboratory Evaluation
   1. Full electrolyte panel, including calcium, magnesium, phosphate
   2. Serum liver function tests and albumin level; cholesterol level
   3. Urine for complete urinalysis with microscopy, spot urine protein and creatinine levels
   4. Serum complement levels (screening with a single CH50 level is adequate)
   5. Serological studies as described above

E. Renal Biopsy and Pathology

1. Most patients with any active sediment should undergo early renal biopsy
2. Consider biopsy for:
   1. Proteinuria >500-1000mg/day
   2. Azotemia, creatinine > ~1.1 mg/dL
   3. Biopsy usually required prior to initiating cytotoxic therapy
   4. Also used for restaging, prognosis, and adjustment of therapy
3. Yields data on WHO Classifciation, Activity Index, and Chronicity Index
4. Activity Index includes semi-quantitative score of 4 active inflammatory lesions:
   1. Glomerular Leukocyte Infiltration
   2. Interstitial Inflammation
   3. Glomerular Karyorrhexis
   4. Cellular Crescents
5. Chronicity Index includes semi-quantitative score of 3 chronic inflammatory lesions:
   1. Glomerular Sclerosis
   2. Interstital Fibrosis
   3. Tubular Atrophy
6. Early treatment will lower requirements for dialysis as well as mortality
7. Approximately 25% of patients will change WHO classification on repeat biopsy [6]
8. Progression to end stage renal disease is ~20% in 10 years

F. Treatment Overview [7,13]

1. Glucocorticoids should be used initially
   1. Nephrotic Syndrome usually responds to 40-60mg po qd of prednisone x 2-4 weeks
   2. Higher doses (2-4mg/kg) are recommended with active sediment in Classes III and IV
   3. Tapering of glucocorticoids should be done early
   4. Patients on steroids should take added calcium + Vit D
   5. Glucocorticoids increase risk of infections (zoster), osteonecrosis, diabetes as well
2. Nearly all patients with lupus nephritis will require cytotoxic immunosuppressive agents
3. Cytotoxic agents can control renal disease and improve outcome [9.10]
   1. Cyclophophamide - mainly for Class IV (and some Class III and V) Disease
   2. Azathioprine - mainly for steroid sparing activity, Class II, III or V Disease
   3. Mycophenolate - relatively well tolerated and may be as effective as cyclophosphamide
   4. Methotrexate is unproven at this time
4. Intravenous Immunoglobulin (IVIg) [8]
   1. May be used for maintenance therapy after cytotoxic therapy induction
   2. Studies in limited numbers of patients with class III and IV disease
   3. Better tolerated than intravenous CYC
5. All patients should be immunized aggressively

G. Cyclophosphamide (CYC; Cytoxan®) [7,9,10]

1. Usual primary agent for treatment of Class IV disease
   1. May be agent of choice for Class III disease with azotemia [9]
   2. Mycophenolate mofetil appears to be a reasonable alternative, safer (see below)
2. CYC is Given in IV Pulses in Lupus Nephritis
   1. IV pulses 500-1000mg/m2 q month x 6 doses, then q3 months for 1-2 years [9]
   2. V CYC for 6 months had significantly higher relapses versus 2 years with above protocol
   3. Serum creatinine was essentially similar in both short and long term groups
   4. Overall rates of complications for two groups were not reported
   5. CYC combined with glucocorticoids are most effective therapy [9,10]
3. Monthly IV CYC is more effective than high dose IV glucocorticoids [9]
4. Oral versus IV CYC
   1. IV monthly doses are more effective than daily oral doses
   2. Daily oral dosing 2-2.5mg/kg/d are more effective than prednisone alone
   3. Lower incidence of gonadal failure in women with oral dosing versus IV [11]
   4. Oral doses have higher incidence of hemorrhagic cystitis than IV
   5. Mycophenolate (below) is better tolerated and may be as effective as oral (or IV) CYC
5. Main Side Effects
   1. Neutropenia - including herpex zoster, sepsis
   2. Nausea, Vomiting
   3. Gonadal Failure (particularly in women given IV CYC)
   4. Alopecia
   5. Development of malignancy or myelodysplasia (long term, particularly leukemias)
   6. Cervical Dysplasia

H. Mycophenolate Mofetil (CellCept®) [12]

1. Impairs de novo purine synthesis
2. Mainly reduces B cell proliferation and antibody production
3. Used in transplantation in place of azathioprine
4. May be as effective as CYC in severe lupus nephritis [12,13]
   1. Used in combination with oral prednsolone (0.8mg/kg/day)
   2. Dose is 1.0-1.5gm po bid
   3. Efficacy comparable to 2.5mg/kg/day oral CYC in severe lupus nephritis
   4. Better tolerated and fewer moderate and severe adverse events than CYC
   5. Reasonable alternative to IV CYC, particularly for maintaining fertility
   6. Reduced risk of infection and late cancers/myelodysplasia compared with CYC
5. Strongly consider use of mycophenolate early after IV CYC
6. May consider mycophenolate first-line in patients with moderate lupus nephritis

I. Azathioprine (Imuran®)

1. More effective than prednisone alone in pooled analyses
2. Not as effective as intravenous cyclophosphamide for Class IV Disease
3. Dose is 2-4 mg/kg/day po
4. Must monitor blood counts
5. Mycophenolate has largely supplanted use

J. Dialysis and Transplantation

1. Overall disease remission in disease in patients who progress to dialysis
2. Lupus patients tolerate dialysis as well as non-lupus patients and have similar outcomes
3. Transplantation is well tolerated and graft survival is similar to non-lupus
4. Recommend that transplant is not done during an acute exacerbation

K. Experimental Therapy

1. Cyclosporine - 2-5mg/kg po qd, adjust for level
2. Plasmapheresis - not effective
3. CD40L / CD40 blockade (soluble receptors, blocking compounds)
4. CD28 Blockers (such as CTLA4-Ig)
5. Anti-CD5 monoclonal antibodies
6. Anti-Lymphokine Therapy

References

1. Somers MJ, Daouk GH, McCluskey RT. 2004. NEJM. 350(15):1550 (Case Record)
2. Lefkowith JB and Gilkeson GS. 1996. Arthritis Rheum. 39(6):894
3. Ledford DK. 1997. JAMA. 278(22):1962
4. Hricik DE, Chung-Park M, Sedor JR. 1998. NEJM. 339(13):888
5. Madaio MP and McCluskey RT. 1998. NEJM. 339(18):1308 (Case Record)
6. Neumann K, Wallace DJ, Azen C, et al. 1995. Semin Arthritis Rheum. 25(1):47
7. Langford CA, Klippel JH, Balow JE, et al. 1998. Ann Intern Med. 128(12):1021
8. Boletis JN, Ionnidis JPA, Boki KA, Moutsopoulos HM. 1999. Lancet. 354(9178):569
9. Gourley MF, Austin HA III, Scott D, et al. 1996. Ann Intern Med. 125(7):549
10. Illei GG, Austin HA III Crane M, et al. 2001. Ann Intern Med. 135(4):248
11. Boumpas DT, Austin HA III, Vaghan EM. et al. 1993. Ann Intern Med. 119:366
12. Chan TM, Li FK, Tang CSO, et al. 2000. NEJM. 343(16):1156
13. Fine DM. 2005. JAMA. 293(24):3053 (Case Discussion)