Transcript class IV

Lupus nephritis
신장내과 R4
강혜란
Introduction


Renal involvement is common in systemic lupus erythematosus (SLE)
(~75%)
Clinically evident renal disease : ~50% of patients with SLE

Abnormal urinalysis with or without an elevated Cr
-> Proteinuria : The most frequently observed abnormality

Emerge soon after diagnosis (commonly within the first 6 - 36 months)

Enhanced risk of developing nephritis earlier in the course of the disease

males, younger patients (< 33 years of age at diagnosis), and non-whites
Pathogenesis

Anti-DNA immune complex formation
 Primarily composed of DNA + anti-DNA
 May also include aggregates composed of chromatin, C1q, laminin, Sm,
La (SS-B), Ro (SS-A), ubiquitin, and ribosomes
 Immune deposits occur in the mesangium, subendothelial, and/or
subepithelial compartments of the glomerulus
Clinical features and Diagnosis

Abnormal urinalysis and/or elevation of the serum creatinine

Diagnosis : confirmed by histopathologic findings on renal biopsy

Detection of renal involvement

Urinalysis with examination of the urinary sediment (hematuria and cellular casts)

Estimation of urine protein excretion (spot urine protein-to-creatinine ratio)

Serum creatinine

Estimated glomerular filtration rate

anti-DNA titers ↑, complement (C3 and C4) levels ↓
 often indicate active lupus, particularly lupus nephritis
Clinical features and Diagnosis

Diagnosis by kidney biopsy

Determining the class of lupus nephritis is important

Treatment is guided by the histologic subtype(ISN/RPS, WHO), degree of activity
and chronicity, and by complicating lesions such as interstitial nephritis and
thrombotic microangiopathy

The clinical presentation may not accurately reflect the severity of the histologic
findings. As an example, proliferative lupus may be present even if the patient
has minimal proteinuria and a normal serum creatinine
Clinical features and Diagnosis

Diagnosis by kidney biopsy

Histopathologic features are highly characteristic of lupus nephritis

Glomerular deposits that stain dominantly for IgG and contain co-deposits of IgA,
IgM ,C3, and C1q, the so-called "full house" immunofluorescence pattern


endocarditis, HIV, hepatitis C, a portosystemic shunt, PSGN
Glomerular deposits simultaneously seen in the mesangial, subendothelial, and
subepithelial locations

Extraglomerular immune type deposits within tubular basement membranes,
the interstitium, and blood vessels

Tubuloreticular inclusions in the glomerular endothelial cells

HIV nephropathy : collapsing focal segmental glomerulosclerosis >> proliferative
glomerulonephritis with immune complex deposition
Classification

modified 1982 WHO system -> 2004 (the International Society of
Nephrology, or ISN, classification)

Six different patterns (or classes) based on kidney biopsy histopathology

Different classes -> distinct histologic, clinical, and prognostic characteristics
Classification


Minimal mesangial lupus nephritis (class I)

IF and/or EM : Only mesangial immune deposits

Without LM abnormalities

Earliest and mildest form of glomerular involvement
Mesangial proliferative lupus nephritis (class II)

LM : mesangial hypercellularity (of any degree) or mesangial matrix expansion

IF, EM : A few isolated subepithelial or subendothelial deposits

Prognosis is excellent , no specific therapy is indicated
Classification

Focal lupus nephritis (class III)

Usually have hematuria and proteinuria, hypertension, GFR ↓, and/or nephrotic
syndrome

LM, IF : < 50 % of glomeruli are affected
 Active or inactive endocapillary or extracapillary glomerulonephritis that is
almost always segmental

EM : subendothelial and mesangial immune deposits

By the inflammatory activity (or chronicity) of the lesions
Class III (A) : active lesions
Class III (A/C) : active and chronic lesions
Class III (C) : chronic inactive lesions with scarring
 Prognosis in class III disease is variable
• Active lesions : endocapillary and (usually) mesangial hypercellularity, crescents,
necrosis, wire loops, hyaline thrombi
• Chronic lesions : segmental and global glomerulosclerosis
Classification

Diffuse lupus nephritis (class IV)

Most common and most severe form of lupus nephritis

Hematuria, proteinuria, nephrotic syndrome, hypertension, GFR ↓ are all
frequently seen

Significant hypocomplementemia (especially C3), elevated anti-DNA levels

LM : ≥50 % of glomeruli are affected
 Endocapillary with or without extracapillary glomerulonephritis
 Segmental (class IV-S, involving < 50 percent of the glomerular tuft)
 Global (class IV-G, involving ≥ 50 percent of the glomerular tuft)
 Class IV (A), Class IV (A/C), Class IV (C)

EM : subendothelial deposits

IF : marked deposition Ig (especially IgG) and complement (especially C3)
Classification

Diffuse lupus nephritis (class IV)
Classification

Membranous lupus nephritis (class V)

Typically present with signs of the nephrotic syndrome

Microscopic hematuria and hypertension

Cr : usually normal or only slightly elevated

LM : diffuse thickening of the glomerular capillary wall

IF, EM : subepithelial immune deposits (either global or segmental involvement)
Classification

Advanced sclerosing lupus nephritis (class VI)

Slowly progressive renal dysfunction in association with proteinuria and a
relatively bland urine sediment

Global sclerosis > 90 % of glomeruli

healing of prior inflammatory injury + the advanced stage of chronic class III, IV,
or V lupus nephritis

immunosuppressive therapy is unlikely to be beneficial
Classification of LN (2004 ISN/RPS)
I
Minimal
mesangial
II
Mesangial
proliferative
III
IV
Focal (<50%)
proliferative
LM: normal
IF: mesangial deposits
LM: mesangial proliferation ± expansion
IF: mesangial deposit without endocapillary proliferation
Focal subendothelial immune deposits + mild mesangial
expansion
Focal endocapillary ± extracapillary proliferation
Diffuse subendothelial immune deposits + mesangial
Diffuse (>50%) alterations
proliferative
Diffuse endocapillary ± extracapillary proliferation
V
Membranous
VI
Advanced
slerotic
Thickened basement membranes + subepithelial immune
deposits
may co-exist with class III or IV
Global sclerosis > 90% of glomeruli without residual activity
Renal biopsy indication

Renal biopsy
 Protein excretion > 500 mg/day
 An active urinary sediment
 hematuria (RBC ≥ 15/HPF, typically dysmorphic) and cellular casts
-> focal or diffuse proliferative glomerulonephritis or membranous lupus

<500 mg/day of proteinuria
 urinalysis every 3-6 months for three years
 every 3 months : anti-ds DNA antibodies and/or hypocomplementemia
Renal biopsy indication

Repeat renal biopsy

a newly active urine sediment after a period of disease quiescence

a rapidly rising serum Cr (which might reflect crescentic disease)

new or worsening nephrotic syndrome in those treated for proliferative lupus
nephritis since such patients may have developed a concurrent membranous
lesion that may require different therapy

a slowly rising serum Cr in patients who also have a urine sediment suggesting
possible low grade disease activity

suspicion of possible renal disease unrelated to lupus (eg, drug-induced acute
interstitial nephritis)
Treatment

Class I LN (minimal-mesangial LN)


Be treated as dictated by the extrarenal clinical manifestations of lupus (2D)
Class II LN (mesangial-proliferative LN)

Proteinuria < 1 g/d as dictated by the extrarenal clinical manifestations of lupus (2D)

Proteinuria > 3 g/d : treated with corticosteroids or CNIs
Treatment

Class III LN (focal LN) and class IV LN (diffuse LN) : initial therapy

Corticosteroids (1A), combined with either cyclophosphamide (1B) or MMF (1B)

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)
Treatment
• Severe class III/IV LN : cyclophosphamide containing protocol for initial therapy
• Less severe proliferative LN: an initial regimen not containing cyclophosphamide should
be considered
Cyclophosphamide

Cyclophosphamide + corticosteroids : reduced development of ESRD (RCT)
-> use of cyclophosphamide in the treatment of class III/IV LN became routine

No significant differences in outcome between i.v. and oral cyclophosphamide

bladder toxicity (chemical cystitis) : only in patients receiving oral
cyclophosphamide -> i.v. cyclophosphamide : standard treatment


To minimize bladder toxicity with oral cyclophosphamide

take cyclophosphamide in the morning

drink extra fluid at each meal and at bed time
use of sodium-2-mercaptoethane (mesna) : minimize the risk of hemorrhagic cystitis
when cyclophosphamide is given as i.v. pulses
Cyclophosphamide

Potential for developing hematologic malignancies later in life, these large
cumulative doses of cyclophosphamide should be avoided


lifetime maximum of 36 g cyclophosphamide in patients with systemic lupus
Dose of cyclophosphamide should be decreased by 20% or 30% in patients with
CrCl 25–50 and 10–25ml/min

Should be adjusted to keep the leucocyte count ≥ 3000/ul

Leukopenia : systemic lupus, as well as cyclophosphamide, can cause
suppression of bone marrow
Cyclophosphamide

To protect fertility

women should be offered prophylaxis with leuprolide, Administration of
leuprolide must be timed carefully in relation to cyclophosphamide to maximize
benefit

Ovarian tissue cryopreservation is an additional, but expensive, option

The efficacy of testosterone in preserving fertility in males is poorly established,
so sperm banking should be offered
Treatment

Class III LN (focal LN) and class IV LN (diffuse LN) : maintenance
therapy

Azathioprine (1.5–2.5mg/kg/d) or MMF (1–2 g/d in divided doses), and
low-dose oral corticosteroids (≤ 10mg/d prednisone equivalent) (1B)

CNIs with low-dose corticosteroids
 patients who are intolerant of MMF and azathioprine (2C)

Maintenance therapy : continued for at least 1 year before consideration is given
to tapering the immunosuppression. (2D)

If complete remission has not been achieved after 12 months of maintenance
therapy, consider performing a repeat kidney biopsy before determining if a
change in therapy is indicated. (Not Graded)

While maintenance therapy is being tapered, if kidney function deteriorates
and/or proteinuria worsens, we suggest that treatment be increased to the
previous level of immunosuppression that controlled the LN. (2D)
Treatment

Class III LN (focal LN) and class IV LN (diffuse LN) : maintenance
therapy

Predictor for remission
 SCr at the start of treatment
 Delay in starting therapy for more than 3 months after clinical diagnosis of LN
 Severity of proteinuria

Monitoring
 Serial measurements of proteinuria and SCr
 resolution of proteinuria : strongest predictor of kidney survival
Treatment

Class V LN (membranous LN)

Normal kidney function, and non–nephrotic range proteinuria
 treated with antiproteinuric and antihypertensive medications, and only
receive corticosteroids and immunosuppressives as dictated by the extrarenal
manifestations of systemic lupus (2D)

Pure class V LN and persistent nephrotic proteinuria
 treated with corticosteroids plus an additional immunosuppressive
agent: cyclophosphamide (2C), or CNI (2C), or MMF (2D), or azathioprine
(2D)
Treatment

General treatment of LN

All patients with LN of any class
 treated with hydroxychloroquine (maximum daily dose of 6–6.5mg/kg
ideal body weight), unless they have a specific contraindication to this drug
(2C)

Hydroxychloroquine : protect against the onset of LN, against relapses of LN,
ESRD, vascular thrombosis, and that it has a favorable impact on lipid profiles

Class VI LN (advanced sclerosis LN)

treated with corticosteroids and immunosuppressives only as dictated by the
extrarenal manifestations of systemic lupus. (2D)
Treatment

Relapse of LN

Relapse of LN after complete or partial remission
 treated with the initial therapy followed by the maintenance therapy that was
effective in inducing the original remission (2B)

If resuming the original therapy would put the patient at risk for excessive
lifetime cyclophosphamide exposure -> non–cyclophosphamide-based initial
regimen be used (Regimen D, Table 28) (2B)

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. (Not
Graded)
Treatment
Treatment

Treatment of resistant disease

Consider performing a repeat kidney biopsy to distinguish active LN from scarring.
(Not Graded)

continue to have active LN on biopsy with one of the alternative initial treatment
regimens (Not Graded)

nonresponders who have failed more than one of the recommended initial
regimens may be considered for treatment with rituximab, i.v. immunoglobulin,
or CNIs (2D)
Treatment

Systemic lupus and thrombotic microangiopathy

antiphospholipid antibody syndrome (APS) involving the kidney in systemic lupus
patients, with or without LN : treated by anticoagulation (target INR 2–3) (2D)

systemic lupus and thrombotic thrombocytopenic purpura (TTP)
 recieve plasma exchange as for patients with TTP without systemic lupus
(2D)
Treatment

Systemic lupus and pregnancy

Women be counseled to delay pregnancy until a complete remission of LN has
been achieved. (2D)

Cyclophosphamide, MMF, ACE-I, and ARBs not be used during pregnancy (1A)

hydroxychloroquine be continued during pregnancy (2B)

LN patients who become pregnant while being treated with MMF be switched to
azathioprine (1B)

if LN patients relapse during pregnancy : treatment with corticosteroids and,
depending on the severity of the relapse, azathioprine (1B)

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. (2D)

administration of low-dose aspirin during pregnancy ; the risk of fetal loss ↓ (2C)
★ Case : F/32 (1725946)
 Present illness
 1주전 시작된 Both 2,3th finger PIP joint pain 및 팔, 등, 서혜부 발진으로
내원
 Past history
 2012’4 : Both leg swelling으로 입원하여 Renal Bx.시행



CBC 4400-9.6/28-4k, BUN/Cr 16/0.67 (eGFR 119.2), Anti-ds-DNA >1450, C3 22, C4 7
24hr protein 9975 mg, microalbumin 1630mg, ACR : 2209.5mcg/g
Lupus nephritis class IV 진단 -> PDL 60mg, MMF 360mg 4T 시작
 2012’8 : PDL 감량 중 Thrombocytopenia 발생




2ndary ITP : IV globulin 50G 투여 및 IV M-PDL 500mg 으로 3일 간 pulse therapy
2012’8’21 – 2012’10’30 : Cyclophosphamide 500mg q 2wks + PDL 50mg/day
CBC 8600-11.4/33-159k, BUN/Cr 12/0.59 (eGFR 123.4)
ACR : 16.6mcg/mg, Anti-ds-DNA 5.25, C3 62, C4 18
 2012’11 ~ : PDL 감량 및 MMF 360mg 4T 유지
 2013’5 ~12 : PDL 5mg, MMF 360mg 4T 유지 -> 이후 f/u loss
 Renal biopsy (2012/4/30)
 Renal biopsy (2012/4/30)
 Renal biopsy (2012/4/30)
 Review of system






 Physical examination
General weakness (-)
Fatigue (-)
Dyspnea (-)
Abdominal pain (-)
Hematuria (-)
Both 2,3th finger PIP joint pain
(+)
 Vital sign
 BP : 110/70 mmHg
 PR : 82 회/min
BT : 36.5℃
RR : 18 회/min
 General appearance
 Not so ill-looking appearance
 Chest
 Normal breathing sound
 Wheezing (-), Rale (-)
 Abdomen
 Tenderness/Rebound tenderness(-/-)
 Back & Extremities
 Pretibial pitting edema(-/-)
 Purpura (+) : 팔, 등, 서혜부
 Lab




CBC 4900-12.3/35.1-10k
BUN/Cr 8.2/0.56 (eGFR 123.8)
E' 142-4.2-103-27
C3 36, C4 9, anti-ds-DNA >102
 RUA : protein 1+, ketone trace, blood 4+, leukocyte 2+, RBC 10-29/HPF,
WBC 10-29/HPF
 24hr urine : protein 452.6mg/day, microalbumin 218.5mg/day
 Diagnosis
 Lupus nephritis class IV, Relapse of LN (Mild)
 Treatment
 Regimen B. Euro-Lupus
 Cyclophosphamide 500mg q 2wks for 3months + PDL 60mg/day
 Hospital course
 HAD 1 : 4900-12.3/35.1-10k : PDL 60mg/day
 HAD2 : 3400-11.4/33.1-10k : Cyclophosphamide 500mg + PDL 60mg/day
 HAD3 : 5200-10.3/29.5-20k : PDL 60mg/day
 HAD4 : 5500-10.5/30.3-45k : PDL 60mg/day
 HAD5 : 5100-10.2/29.7-57k : PDL 60mg/day, Leuprorelin 3.75mg sc
 HAD6 : 4100-10.5/30.1-65k : PDL 60mg/day, Discharge
Classification of LN (2004 ISN/RPS)