Tomisaku Kawasaki *
Department of Pediatrics.*
AP, 13 years girl
- H/o fever, joint pain, rash
- Inv Normal renal fn, urine Rm RBCs+++
- Lost to follow up
- Anasarca, rashes, Anemia - 1 BT given
- BP = 120/80
- Hb = 7, TLC 4800, Plat 68,000 BUN 47, Cr 5.8
- Urine RM 4+ protein, 10-12 WBC, 1-2 RBC
- C3 33.1, dsDNA 67.1, US RK 12.2, LK 12.8
- J Bx Stage IV
- Rx MP, Oral Prednisalone, IVCP pulses
- CAPD 1/2004
- Peritonitis - Catheter removal 4/2004
- Biweekly HD
- Pericarditis, Coombs + Hem Anemia
- Rx Prednisalone and IVCP
- Kidney Tx 14/9/2004
- Current Immunosupp Csa, MMF, Prednisalone
- Last FU stable S Cr 0.7
- Serious manifestation of SLE
- Usually arises within 5 years of diagnosis
- Renal failure rare before ACR criteria are met
- Renal manifestations are more common in pediatric SLE patients than in adults
- Histological evidence in absence of clinical manifestations of renal disease
- 30-90% of children
- More severe in Asians and Blacks
- Males - Increased prevalence of clinical renal disease with a worse prognosis
- Genetic factors
C1Q, C1R, and C1S deficiencies
Low-affinity phenotype (homozygous for R131 allele; 131R/R)
- Immunologic factors
- Asymptomatic - laboratory abnormalities
- Symptom Of active SLE, including fatigue, fever, rash, arthritis, serositis
- Peripheral edema
- Headache, dizziness, visual disturbances, and signs of cardiac decompensation
- Blood urea nitrogen testing
- Serum creatinine level
- Urinalysis (to check for protein, RBCs, and cellular casts
- Creatinine clearance
- 24 hr urinary protein excretion (spot urine for creatinine and protein)
- Tests of SLE disease activity
anti-dsDNA, C3, C4, and CH50, ESR, CRP
- Renal biopsy - any patient with SLE who has clinical or laboratory evidence of active nephritis, especially with the first episode of nephritis.
- Normal renal biopsy findings from light, Immunofluorescence, and electron microscopy indicate an essentially normal kidney.
- No clinical evidence of renal disease is present.
Class II : Mesangial glomerulonephritis
- Class IIa - Mild Mesangial proliferation
- Class IIb - Moderate mesangial proliferation
- Light microscopy
Class IIa - Mild Mesangial hypercellularity
Class IIb - Definite glomerular mesangial hypercellularity confined to the centrilobular areas
- Immunofluorescence Immune deposits are confined to the mesangium.
- Electron microscopy Immune deposits are confined to the mesangium.
- Clinical manifestations. These patients have mild renal disease such as asymptomatic hematuria or proteinuria that usually does not warrant specific therapy.
Class III - Focal segmental proliferative glomerulonephritis
- Class IIIa - With active necrotizing lesions
- Class IIIb - With active and sclerosing lesions
- Class IIIc - With sclerosing lesions
LM Proliferative inflammatory glomerular lesions with variable amounts of leukocyte infiltration, mesangial and endothelial cell proliferation, necrosis, and sclerosis are present. A portion (segmental) of less than 50% of all glomeruli are involved.
If Diffuse mesangial and irregular capillary wall immune deposits are present.
EM Subendothelial and mesangial immune deposits are present.
- Clinical manifestations. Many patients present with active generalized SLE and mild-to-moderate renal disease with hematuria and moderate proteinuria. A significant minority show worsening renal function and may progress to class IV lupus nephritis.
Class IV - Diffuse proliferative glomerulonephritis
Class IVa - Without segmental lesions
Class IVb - With active necrotizing lesions
Class IVc - With active and sclerosing lesions
Class IVd - With active sclerosing lesions
LM Proliferative inflammatory glomerular lesions with endothelial cell proliferation result in the loss of capillary space, leukocyte infiltration, variable amounts of necrosis, crescent formation, and sclerosis. Hyaline deposits are present in the capillary wall ("wire loops") or vessel ("hyaline thrombi"). More than 50% of glomeruli are diffusely involved.
ImF Irregular immune deposits are present in the mesangium and capillary walls.
- Electron microscopy Large subendothelial and mesangial immune deposits and, occasionally, subepithelial and intramembranous deposits, may be found.
- Clinical manifestations. These patients usually present with clinical evidence of renal disease, including hypertension, edema, active urinary sediment, worsening renal function, and nephritic range proteinuria.
- Class V - Diffuse membranous glomerulonephritis
- Class Va - Pure membranous glomerulonephritis
- Class Vb - Associated with mesangial hypercellularity
LM: Diffuse thickening of glomerular basement membrane occurs, without inflammatory infiltrate. With special staining, including silver and trichrome, one may see subepithelial deposits and surrounding basement membrane spikes. Membranous lesions are associated with proliferative lesions, either focal or diffuse (membranoproliferative glomerulonephritis).
ImF: Diffuse capillary wall and frequently mesangial immune deposits are present.
EM: Subepithelial and intramembranous immune deposits are present. Subendothelial deposits are present only in association with a proliferative component.
Clinical manifestations: These patients have clinical and laboratory features of nephritic syndrome, usually without manifestations of active SLE.
Class VI - Sclerosing Glomerulonephritis
- LM: This is characterized by advanced glomerular sclerosis, interstitial fibrosis, and tubular atrophy, all morphological manifestations of irreversible renal injury. Proliferative glomerular lesions are remnants or are absent.
- Clinical Manifestations: These patients usually have significant renal insufficiency or endstage renal disease and are unlikely to respond to medical therapy.
Pathologic Features used to Determine Activity and Chronicity Indices:
|| Chronicity Index
| Glomerular features
|o Endocapillary proliferation
o Leukocyte infiltration
o Subendothelial hyaline deposits
o Fibrinoid necrosis/karyorrhexis
o Cellular crescents
|o Glomerular sclerosis
o Fibrous crescents
| Tubulointerstitial features
|o Interstitial inflammation
o Tubular atrophy
| Interstitial fibrosis |
Therapies for renal biopsy-specific Pathologic lesions:
- Class I lesions require no specific therapy
- Class II lesions - RX of extra renal manifestations
- If proteinuria > 1000 mg/d, elevated anti-dsDNA is present, and low complement levels are present, the patient could have a proliferative component not sampled in the biopsy specimen Consider prednisone in low-to-moderate does (i.e., 0.5-1.0 mg/kg/d) for 1-3 months, with subsequent taper.
Treatment of Proliferative (Class III & IV) Lupus Nephritis
Mild to moderate
Prednisolone (1 mg/kg/day): for 8 weeks
- Compete response: Taper to EOD (0.25 mg/kg) X approx. 2 years and monitor
- If no or partial response : Start monthly pulse CY
Moderate to Severe
- Prednisolone + monthly pulse CY (0.5 g/m2 - 0.75 g/m2) x 6 mths.
- Dose may be - to 1 gm/m2 unless TLC < 1500.
Treatment of proliferative (Class III & IV) Lupus Nephritis
- Prednisolone + monthly pulse CY
- Pulse MP (1 g/m2 x 3 days) + Prednisolone
- Pulse CY 3 mths + prednisolone EOD (0.25 mg/kg)
- Prednisolone + Azathioprine (2 mg/kg/day)
- Pred + MMF (1100 mg/m2/day)
- Pred + oral CY (2 mg/kg/day)
- Pred + Cyclosporine (3-5 mg/kg)
NIH Trials (1991)
Boumpas et al (1992): 65 pts
|| : Pulse IV MP x 6 mths (monthly)
| Group II
|| :Pulse IV CY x 6 mths (monthly)
| Group III
||:Pulse IV CY x 6 mths (monthly) & IV Cy q 3 mthly x 2 yrs.
Doubling of s. creatinine 15% group III, 50% in group I
Relapse free 90% group III, 40% group II
Chan et al (1999)
|| - Prednisolone + daily Cyclophosphamide (CY)
| After 6 months
|| - CY replaced by Aza
| At 12 months
|| - CR 55%, PR 35%. |
Austin et al
- Alternate day prednisolone
- Alternate day Pred + Alt. Month pulse Cyclophosphamide (CY)
- Alt. Day Pred + Cyclosporine
Best results - in group with pulse CY
- Induction with IV MP followed by oral pred (20 mg/day) + Aza (2 mg/kg/day)
- Pulse MP and pulse CY (better than CY alone)
- Cyclosporine (5 mg/kg/day useful in maintenance phase
Conteras et al (2002) MMF in Lupus DPGN
Induction IV CY monthly + Prednisolone x mths.
Group I, IV CY q 3 mths + Pred (0.5 mg/kg/day)
GroupII Aza + Pred
Group III. MMF (500-3000 mg/day) + Pred
MMF & Aza better tolerated than IV. CY
MMF in lupus DPGN
- Chan et al (2000)
- Group A : 21 pts MMF (2 g/day) + Prednisolone x 6 mths
- Group B : 21 pts oral CY + Prednisolone x 6 mths
|| Aza + Pred
|| x 6 mths
|| Group A
|| Group B
Which of the Cytotoxic drugs in superior ?
No controlled trials have compared them in terms of efficacy and toxicity
- Most studies found no difference in renal or patient survival
- CY associated with severe side effects (gonadal toxicity) IV probably better than oral
- Aza does not affect reproductive ability
- CY contraindicated during pregnancy
- Comparable efficacy
- MMF & Aza better tolerated than IV, CY
Class V : Membranous nephropathy
Some controversy exists
- Variable renal outcome
- Uncertain natural history
- Mixing of pure membranous together with MPGN
- Associated with increased risk of ESRD & death
- Survival 5 yrs 85%
10 yrs 72%
- Nephrotics - 5 fold | risk of MI
-| Risk of thromboembolism
Class V lesions
- Prednisone for 1-3 months, followed by tapering for 1-2 years
- Immunosuppressive drugs - worsening renal function or a proliferative component is present on renal biopsy samples
End-stage renal disease
3-month period of dialysis
- Hemodialysis is preferred over peritoneal dialysis (higher anti-dsDNA levels, more thrombocytopenia in PD)
- Kidney transplantation
New prospects for treatment of lupus nephritis
- Fludarabine: Halogenated adenosine analogues
- Combination chemotherapies:
- Cyclophosphamide + Azathioprine
Methotrexate + Aza + CsA + CY
Problems: Cumulative toxicity
Bone marrow transplantation and ablative chemotherapy with stem cell reconstitution
- High dose chemotherapy : very high dose of CY (10 times higher than presently used)
Followed by G-CSF
Preliminary results promising
- T-B cell co stimulatory blockade
B cell activation - autoantibody production
anti - CD 154 & CTLAG - Ig modulate B cell activation
Experimental data beneficial if given alone or in combination
Human trials started
- Complement inhibitors: monoclonal antibody to C5b lowers anti dsDNA antibody.
Human trials started (initial data not very promising)
- Plasmapheresis: not helpful even in combination with CY (controlled trials)
- Total lymphoid irradiation: may be tried in severe lupus nephritis
10 year follow up (Genovese, 2002)
43% did not progress to ESRD
- Aggressive control of BP with ACEI & diuretics
- Control of hyperlipidemia
- Prevention of steroid induced osteoporosis
- Avoid pregnancy during cytotoxic treatment
- ESRD: renal transplantation may be done after 3 months of start of dialysis
When can we stop treatment in lupus nephritis?
- Abrupt cessation of treatment can result in severe flares of activity
- Treatment should be tapered off gradually in pts with quiescent disease
- Risk of flares drops with time
Pointicelli et al 2000
|| 1st 5 yrs
|| 5th - 10th yrs
|| 11th - 15 yrs
|| 0.28 |
- Therapy can be stopped if
- No flares for at least 3 yrs
- S. creatinine is normal, proteinuria <1 gm/day, urine sediment is inactive
- Slow tapering
- Careful monitoring
- ESR, anti-dsDNA, and C3 and C4 to monitor SLE disease activity.
Mortality / Morbidity
- 5- and 10-year survival rates to 85% and 73%, respectively
Renal disease - HT, Nephrotic syndrome, CRF
Treatment - related
Drugs - Pred, Cyclophosphamide
- 90 children with SLE - 72% had nephritis
At a mean follow-up of 4.1 years
62% were in clinical remission
24.5% were in partial remission
5.4% had active nephritis
5.4% had died
2.7% patients were lost to follow-up
Overall prognosis was good with 95% survival at 4 years.
- Delay in treatment of more than 5 months from onset of nephritis
- Young age at onset of nephritis
- Male sex
- Black racial background
- Nephrotic syndrome
- Elevated creatinine level (> 3 mg/dL) at presentation
- Persistently elevated anti-dsDNA and low C3 and C4 levels
- Renal biopsy findings showing diffuse proliferative glomerulonephritis or high chronicity index
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