CONNECTIVE TISSUE DI SEASES

RENAL & URINARY TRACT DISEASES

Irma A. Lee, MD
Department of Obstetrics and Gynecology
Faculty of Medicine and Surgery


SYSTEMIC LUPUS ERYTHEMATOSUS

Autoantibodies
Antibodies directed against self or normal tissues
Maybe stimulated by bacterial or viral injury of susceptible
tissues tissue destruction VIA
1. CYTOTOXIC MECHANISM antibody attachment
to specific surface antigen CELL INJ URY
2. IMMUNE COMPLEX MECHANISM antigen-
antibody complex attaches to susceptible tissues
CASCADE OF CHEMOTACTIC RELEASE

Human Leukocyte Antigen (HLA)
Genetic loci code for cell-surface glycoprotein for self and
non-self recognition
Class I HLA-A, HLA-B, HLA-C
Class II HLA-DR, HLA-DQ, HLA-DP
Systemic Lupus Erythematosus
Heterogenous syndrome with genetic loci is on 1q and 6p
Overactive lymphocytes autoantibody production
Prevalent in women; 1:500 during child-bearing






Laboratory Tests:
1. Antinuclear antibody (ANA) best screening but not specific
2. Double-stranded DNA (dsDNA) antibodies Smith (Sm)
antigen specific for SLE
3. CBC anemia, leukopenia, thrombocytopenia
4. Proteinuria, casts
5. APTT
6. Rheumatoid factor assay



Goals During Pregnancy
1. 6 months remission prior to conception
2. No renal involvement
3. Prevent superimposed pre-eclampsia
4. No APA activity

Pharmacologic Therapy
1. Non-steroidal anti-inflammatory drug
2. Low dose aspirin
3. Prednisone 1-2 mg/kg/day tapering to 10-15 mg/day
4. Immunosuppressive/Cytotoxic drugs (Azathioprine and
Cyclophosphamide)
5. Antimalarial (Hydroxychloroquine)
- skin disease
6. High-dose glucocorticoids 1000mg/day for three days
- lupus flare
Major Complications
1. Infection
2. Lupus flares
3. End-organ failure
4. Cardiovascular disease

DRUG-INDUCED LUPUS
Lupus-like syndrome
Procainamide
Quinidine
Hydralazine
Alpha-methyldopa
Phenytoin
Phenobarbital


ANTI-PHOSPHOLIPID ANTIBODY SYNDROME

A P A S
Autoimmune disorder characterized by circulating antibodies against
membrane phospholipid and one or more specific clinical syndromes

Classification
Primary APS
- occurs alone with associated thrombo-embolic
phenomena, thrombocytopenia, adverse obstetrical outcome
APS secondary to SLE, drugs, infections, malignancies

Clinical Manifestations
Pregnancy wastage due to decidual/placental
thrombosis or immune complex deposition
Pre-eclampsia in 20-30%
IUGR (50%), associated with moderate to high titer ACA
IgG, history of fetal demise, prednisone therapy
Preterm delivery (25-40%) secondary to PPROM in
patients on steroids
Thrombosis (20-60%)
Venous lower limb 55%
Arterial involves the brain in 50%, heart 25%,
renal 25%
Vascular occlusion from mitral or aortic valve 49%



C Cl li in ni ic ca al l C Cr ri it te er ri ia a f fo or r D De ef fi in ni it te e A AP PS S
Vascular Criteria confirmed by imaging, Doppler, or
histopathology
Pregnancy Morbidity
a. > 1 unexplained death of a normal fetus > 10 weeks
b. > 1 premature births < 34 weeks due to pre-eclampsia
or placental insufficiency
c. > 3 consecutive spontaneous abortions < 10 weeks

International Consensus Statement on
Preliminary Criteria for
Classification of APS
Wilson, Arthritis Rheuma 1999

L La ab bo or ra at to or ry y C Cr ri it te er ri ia a f fo or r D De ef fi in ni it te e A AP PS S
1. Lupus Anticoagulant (LAC)
> 2 6 weeks apart
Prolonged phospholipid-dependent coagulation (aPTT,
DRVVT, KCT, DPTT, Textarin Time)

2. Anticardiolipin Antibodies (ACA)
> 2 6 weeks apart
Medium to high titer IgG or IgM by ELISA

International Consensus Statement on
Preliminary Criteria for the
Classification of APS
Wilson, Arthritis Rheuma 1999

A AC CA A ( (E EL LI I S SA A) ) : : 1 10 0- -3 30 0% % o of f A AC CA A ( (+ +) ) w wi il ll l b be e L LA AC C ( (+ +) )
- -- -- - p pr re ed di ic ct ti iv ve e o of f a ad dv ve er rs se e f fe et ta al l o ou ut tc co om me e

RESULT IgM (MPL) IgG (GPL)
Negative < 10 < 8
Low Positive 10-19 8-19
*Mid Positive 20-50 20-80
*High Positive > 50 > 80

LAC: 70-80% LAC (+) will be ACA (+)
--- predictive of thrombosis

P Pr re ev va al le en nc ce e o of f A AC CA A
L Lo ow w t ti it te er r A AC CA A I I g gG G
0-3% non-pregnant women
2-4% of pregnant women
4-5% with single unexplained early pregnancy loss
M Mo od de er ra at te e t to o H Hi ig gh h t ti it te er r A AC CA A I I g gG G
5 20% > 3 spontaneous pregnancy losses

C Cl la as ss si if fi ic ca at ti io on n S Sy ys st te em m f fo or r W Wo om me en n w wi it th h A AP PS S
1. D De ef fi in ni it te e o or r C Cl la as ss si ic c A AP PS S
- Patients with LA or medium to high levels of IgG or
IgM ACL antibodies and fetal death, recurrent
pre embryonic or embryonic pregnancy with
thrombosis or neonatal death secondary to
preeclampsia severe or fetal distress

2. Syndrome of low levels of IgG or IgM ACL antibodies associated
with fetal death or recurrent, pre embryonic or embryonic pregnancy
loss

3. Syndrome of APL other than LA and ACL antibodies associated
with fetal death or recurrent pre embryonic or embryonic pregnancy
loss









Proposed mechanisms in pregnancy loss in APS

TARGET

MECHANI SM

Eicosanoids

Decrease prostacyclin & increase in
thromboxane production by
endothelial cells

Antithrombin III

Inhibition of heparan sulfate heparin-
dependent activation of
antithrombin III

Protein C & S

Inhibition of the activation of Protein
C-Protein S- pathway

Endothelial cells
and platelets

Activation of endothelial cells &
platelets; inc expression of
adhesion molecules

Annexin V

Reduce annexin V production,
inhibition of its function in
placenta by APL antibodies


T Th he er ra ap pe eu ut ti ic c a ap pp pr ro oa ac ch h t to o A AP PA AS S i in n p pr re eg gn na an nc cy y
O Ob bj je ec ct ti iv ve es s: :
1. Improve maternal and fetal-neonatal outcome by preventing
pregnancy loss, pre-eclampsia, placental insufficiency and
preterm birth
2. Reduce or eliminate maternal thrombotic risk
Branch and Khamashta
ACOG 2003
M Ma an na ag ge em me en nt t o of f C Cl la as ss si ic ca al l A AP PS S
1. Preconception Counseling

Risks of fetal loss
Thrombosis or stroke
Preeclampsia
IUGR
Preterm delivery

2 2. . T Tr re ea at tm me en nt t R Re eg gi im me en ns s

Prevention of pregnancy loss
Thromboprophylaxis
Prevention of complications of placental insufficiency
Postpartum treatment


P Pr re ev ve en nt ti io on n o of f P Pr re eg gn na an nc cy y L Lo os ss s

1. High-dose Prednisone and Low-dose Aspirin
(40 mg/day + 80 mg/day)

Cowchock n = 20 LDA 80 mg/day 75%
*
+ Prednisone 20 mg BID
Silver n = 34 LDA 80 mg/day 100%
*

+ Prednisone 20 mg BID

*more fetal side effects

2. Aspirin and Heparin


Kutteh n = 50


AAS 80 mg/day 80%
+Heparin 5,000 U bid
Rai n = 90



AAS 75 mg/day 71%
+ Heparin 5,000 U bid

R Re ec cu ur rr re en nt t P Pr re eg gn na an nc cy y L Lo os ss s w wi it th h A An nt ti ip ph ho os sp ph ho ol li ip pi id d A An nt ti ib bo od dy y :
A A S Sy ys st te em ma at ti ic c R Re ev vi ie ew w o of f T Th he er ra ap pe eu ut ti ic c T Tr ri ia al ls s

Combination therapy with Aspirin and Heparin may reduce
pregnancy loss in women with antiphospholipid antibodies by
54%. Further large, randomized controlled trials with adequate
allocation are necessary to exclude significant adverse events


Empson et al
ACOG J anuary 2002

T Th hr ro om mb bo op pr ro op ph hy yl la ax xi is s



P Pr re ev ve en nt ti io on n o of f C Co om mp pl li ic ca at ti io on ns s o of f P Pl la ac ce en nt ta al l I I n ns su uf ff fi ic ci ie en nc cy y
I I V VI I g g ---- salvaged therapy

Branch et al n = 16 LDA 80 mg/day 100%
+ Heparin 7500 U BID
+ IVIg
P Po os st tp pa ar rt tu um m T Tr re ea at tm me en nt t
S So od di iu um m w wa ar rf fa ar ri in n for 6 weeks postpartum
L Li if fe el lo on ng g A An nt ti ic co oa ag gu ul la at ti io on n 2.5 to 3.0 International
Normalized Ratio (INR)

Management of Patients with Low levels of Antibodies
Pattison n=40 AAS 75 mg/day 80%
vs
placebo 85%

* therapy remains controversial
neither LDA nor heparin are needed for successful pregnancy


ALGORITHM FOR THE MANAGEMENT OF APAS

Woman Diagnosed w/
APS desires pregnancy

Preconception consultation w/
Obstetrician & rheumatologist;
Inititate low dose aspirin

TVS to confirm live
embryo at 5.5-6.5 wks AOG

Initiate heparin treatment

CLINICAL CARE DIAGNOSTIC TESTS

Prenatal visit q 2-4 wks
until 20-24 wks then q
1-2 wks, thereafter

Monitor for fetal death,
Preeclampsia & IUGR

Rheumatology visit q 2-4 wks



SCLERODERMA

SYSTEMIC SCLEROSIS (SCLERODERMA)
Multisystem disease with fibrosis and thickening of the skin and
visceral organ due to accumulation of collagen


TYPES OF SYSTEMIC SCLEROSIS
1. Overlap Syndrome Systemic Sclerosis with features of other
connective tissue disease
2. Mixed Connective Tissue Disease Syndrome with Lupus,
Systemic Sclerosis, Polymyositis, Rheumatoid Arthritis, high titers
of Anti-RNP antibodies

CLINICAL MANIFESTATIONS
1. Reynauds Phenomenon
2. Swelling of distal extremities and face
3. Fullness & epigastric burning pain
4. Dyspnea
5. Renal
6. CREST

MATERNAL COMPLICATIONS
1. Hypertension
2. Renal Failure
3. Cardio-pulmonary complications as a result of pulmonary
interstitial fibrosis with vasculopathy Pulmonary hypertension

FETAL COMPLICATIONS
1. Preterm deliveries
2. Fetal growth restriction
3. Increase perinatal deaths

GOALS OF THERAPY
1. Improve organ function
2. Relieve symptoms

DRUG THERAPY
1. Corticosteroids myositis, pericarditis, hemolytic anemia
2. ACE Inhibitors relief of hypertension and renal failure



Obstetric ultrasound q 3-4
weeks from 17-20 wks of
gestation
Assess fetal growth and AFI
Fetal surveillance weekly
fr 30-32 wks earlier if
placental
Insufficiency is suspected
RENAL AND URINARY TRACT DISEASES


URINARY TRACT INFECTIONS
1. Asymptomatic bacteriuria
2. Cystitis/Urethritis
3. Pyelonephritis

ASYMPTOMATIC BACTERIURIA
Most common; 2-7% of pregnant women
25% infected symptomatic
100,000 organisms per mL = Bacteriuria
Leukocyte esterase-nitrite dipstick cost-effective
Complications : Preterm births, LBW, Hypertension, Maternal
Anemia



CYSTITIS AND URETHRITIS
Dysuria, urgency and frequency
Pyuria, bacteriuria, hematuria
3-day regimen
Chlamydia Trachomatis cause of urethritis w/o growth on
culture

ACUTE PYELONEPHRITIS
Occurs at the 2
nd
trimester unilaterally and right-sided
Characterized by fever, chills, and lumbar pain CVA
tenderness
Organisms
E.Coli 75-80%
Klebsiella 10%
Enterobacter 10%
Proteus 10%

ACUTE PYELONEPHRITIS
Bacteremia Sepsis syndrome
Ampicillin + Gentamicin, Cefazolin or Ceftriaxone




NEPHROLITHIASIS DURING PREGNANCY
Pregnancy does not increase risk for stone formation
Presents with gross hematuria
Sonography confirms suspected stone
Intravenous Hydration & Analgesics
Lithotripsy



ACUTE NEPHRITIC SYNDROME
Characterized by hematuria and proteinuria with renal
insufficiency and salt-water retention edema, hypertension and
circulatory congestion
Acute poststreptococcal glomerulonephritis
Membranous IgA and mesangial glomerulonephritis are seen on
renal biopsy
Associated with fetal loss and perinatal mortality, preterm delivery
and growth restriction


A series of greetings: thanx to KC we have this handout, belated happy birthday
to J aymie, congrats to Luwi and his team for being 1
st
in the quiz bee, and hello
to lani and millet The next two weeks will be a blur so good luck to everyone!

When something comes along just once in a lifetime, screw everything else.
-Steph
We must be bold, beautiful & without regret. -by liz A2007