Lupus Nephritis in Pregnancy - NYU Langone Health · Lupus Nephritis in Pregnancy Nicola Sumorok...
Transcript of Lupus Nephritis in Pregnancy - NYU Langone Health · Lupus Nephritis in Pregnancy Nicola Sumorok...
Lupus Nephritis in PregnancyNicola Sumorok
Nephrology Grand Rounds, August 16th, 2011
Outline
• Normal physiology of pregnancy
• CKD in pregnancy• Lupus nephritis in pregnancy• Pre‐eclampsia
Normal Physiology of Pregnancy
• Kidneys play a major role in adapting to pregnancy and needs
of the fetus
• Renal hemodynamic adjustments:• Marked vasodilation decrease in BP
• Increase in RBF by up to 80% above baseline• Increase in GFR by about 50%• Retention of Na (about 900 mEq) increased plasma volume
• Stimulation of RAS system –
maintains BP
• Increased CO from decreased afterload and increased HR
• Overall increase in size of the kidneys by 1‐1.5cm
Normal Physiology of Pregnancy
• Nonhemodynamic Alterations:
• Progesterone stimulates meduIlary respiratory center
• Increase in RR and TV respiratory alkalosis (dec
PCO2)
• Partially compensated, resulting in low serum
bicarbonate
• Lower osmotic threshold for thirst and ADH release
lower serum osm and Na concentration
Normal Physiology, in Summary…
• The renal adaptation to pregnancy is critical to ensure appropriate volume expansion and increased perfusion to
meet the needs of the developing fetus and placenta.
• Vasodilation, lower blood pressure, and increased cardiac output are the most obvious consequences of this process.
• Theoretically, the adaptive physiologic changes in pregnancy (especially increased GFR and Renal plasma flow) render a
woman with renal disease vulnerable to deterioration
CKD in Pregnancy
Jones, et al• 82 pregnancies in 67 women with primary renal disease
• Cr > 1.4 prior to pregnancy or 1st
antepartum visit
• 90% with known chronic GN or chronic tubulointerstitial disease
Jones D, Hayslett J. Outcome of Women in Pregnancy with Moderate
or Severe Renal Disease. NEJM,
1996; 335: 226‐232.
Results
Jones D, Hayslett J. Outcome of Women in Pregnancy with Moderate
or Severe Renal Disease. NEJM,
1996; 335: 226‐232.
Trends in Serum Cr
Jones D, Hayslett J. Outcome of Women in Pregnancy with Moderate
or Severe Renal Disease. NEJM,
1996; 335: 226‐232.
Renal function 6 months post‐partum
Jones D, Hayslett J. Outcome of Women in Pregnancy with Moderate
or Severe Renal Disease. NEJM,
1996; 335: 226‐232.
Outcomes and Neonatal Complications
Jones D, Hayslett J. Outcome of Women in Pregnancy with Moderate
or Severe Renal Disease. NEJM,
1996; 335: 226‐232.
In Summary…
• HTN and high‐grade proteinuria were maternal complications
in women with moderate to severe renal insufficiency
• Pregnancy related loss of renal function in nearly 50% of the women
• 10% had rapid progression to ESRD within 6 months after
delivery –
associated with Cr > 2.0 at beginning of pregnancy
• Fetal survival only moderately reduced, but obstetrical
complications in > 50%
Lupus Nephritis in Pregnancy
•Questions:• What is the effect of lupus nephritis on maternal and fetal
outcomes?
• What is the effect of pregnancy on renal disease in patients with
pre‐existing lupus nephritis?
Smyth, et al.
• Systematic literature review of pregnancy outcomes in
women with SLE and a meta‐analysis of the association of
lupus nephritis with adverse pregnancy outcomes.
• 1980‐2009: Thirty‐seven studies with 1842 patients and 2751 pregnancies were included
• Primary fetal outcome: Unsuccessful pregnancy (spontaeous
abortion, stillbirth, neonatal death)
• Maternal complications: Death, stroke, HTN, preeclampsia or
eclampsia, nephritis, lupus flares
Smyth, et al. A Systematic Review and Meta‐Analysis of Pregnancy
Outcomes in Patients with Systemic Lupus Erythematosus and Lupus
Nephritis. Clin J Am Soc Nephrol; 5: 2060–2068, 2010.
Smyth, et al.
Smyth, et al. A Systematic Review and Meta‐Analysis of Pregnancy Outcomes in
Patients with Systemic Lupus Erythematosus and Lupus Nephritis. Clin J Am Soc
Nephrol; 5: 2060–2068, 2010.
Results:29 Case‐series5 Case‐controls studies3 Cohort studies‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐12 Prospective25 Retrospective
Smyth, et al
• Fetal Complications:• 23.4% of pregnancies were unsuccessful• Among live births, 39.4% premature
• Maternal Complications:• Lupus flare 25.6%• HTN 16.3%• Nephritis 16.1%• Pre‐eclampsia 7.6%
• Severe complications (ecclampsia, stroke, death) 1%
Smyth, et al. A Systematic Review and Meta‐Analysis of Pregnancy Outcomes in
Patients with Systemic Lupus Erythematosus and Lupus Nephritis. Clin J Am Soc
Nephrol; 5: 2060–2068, 2010.
Smyth, et al
Conclusions…
• Active lupus nephritis increases the risk for adverse pregnancy outcomes, particularly premature birth and hypertension
• The findings support the current recommendations calling for
avoidance of pregnancy until all manifestations of nephritis
are quiescent
• History of nephritis was associated with higher rates of preeclampsia, thus emphasizing the need for a multispecialty
approach in the care of these patients with respect to close
monitoring and early recognition of clinical signs of pre‐
eclampsia.
Pre‐eclampsia
Pre‐eclampsia: Background• Definition: Development of HTN (BP > 140/90 mmHg),
proteinuria (>300mg/24h), and edema after the 20th
week of
pregnancy• Early = < 34 weeks vs. Late = > 34 weeks• Severe:
• CNS dysfunction (headaches, blurry vision, seizures, coma)• Marked elevations in BP (>160/110 mmHg)• Severe proteinuria (>5g/24h)• Oliguria or renal failure• Pulmonary edema• Hepatocellular injury (ALT >2x ULN)• Thrombocytopenia (Plts < 100,000/ul)• DIC• Treatment = Delivery of the placenta
Pre‐eclampsia: PathophysiologyNormal Physiology:•Extravillous cytotrophoblasts
enter the lining of the uterus
between 6 and 18 weeks•The cytotrophoblasts meet the
spiral arteries, which enlarge to
form high capacitance blood
vessels•These blood vessels help
supply the placentas needs
after 20 weeks
Pre‐eclampsia:•Extravillous trophoblast cells
do not meet the spiral arteries•Leads to altered vascular flow
‐> placental ischemia
Hypothesis of the pathophysiology of pre‐eclampsia
Noris, et al. Mechanisms of Disease: pre‐eclampsia. Nature Clinical Practice
Nephrology. 2005; 1: 98‐114.
sFlt‐1: Soluble fms‐like tyrosine kinase 1
• Soluble vascular endothelial growth factor (VEGF) receptor 1• Binds and inactivates proangiogenic VEGF and PlGF• Acts by inhibiting local VEGF signaling in target organs
including the kidney, brain, and liver where VEGF is
constitutively expressed
• Levels of sFlt‐1 and PlGF altered before clinical onset of pre‐ eclampsia and correlate with severity
Clinical Manifestations
• Hypertension (normal vasodilation of pregnancy
counteracted)
• Proteinuria (glomerular endothelial damage)
• Cerebral edema, seizures
• Reflects widespread endothelial dysfunction with vasoconstriction and end‐organ ischemia
Levine, et al
• Nested case‐control study involving healthy nulliparous women
• 175 women who developed pre‐eclampsia
• One normotensive matched control for each woman with pre‐
eclampsia
• Total of 120 pairs randomly chosen for analysis
• ELISAs for human sFlt‐1, free PlGF, free VEGF
Levine, et al. Circulating Angiogenic Factors and the Risk of Preeclampsia. NEJM.
2004; 350: 672‐83.
Levine, et al
Levine, et al. Circulating Angiogenic Factors and the Risk of Preeclampsia. NEJM.
2004; 350: 672‐83.
Levine, et al
Levine, et al. Circulating Angiogenic Factors and the Risk of Preeclampsia. NEJM.
2004; 350: 672‐83.
Endoglin
• Co‐receptor for transforming growth factor β1 and β3 (TGF‐
β1 and TGF‐ β3)
• Highly expressed on cell membranes of vascular endothelium
and syncytiotrophoblasts
• Placental endoglin found to be upregulated in pre‐eclampsia,
releasing soluble endoglin into the maternal circulation
• Soluble endoglin is an anti‐angiogenic protein thought to inhibit TGF‐ β1 signaling in the vascular endothelium
Levine, et al
Levine, et al. Soluble Endoglin and Other Circulationg Antiangiogenic Factors in
Preeclampsia. NEJM. 2006; 355: 992‐1005.
Thadani, et al• In vitro experiment: Apheresis column made of dextran
sulfate
• In theory, binds positively‐charged sFlt‐1• 2 sources:
• Spiked sFlt‐1 into disgarded human blood
• Human amniotic fluid
• Measured pre‐
and post‐
levels of sFlt‐1 after running fluid
through column
Thadani, et al. Pilot Study of Extracorpeal Removal of Soluble Fms‐Like Tyrosine Kinase 1
in Preeclampsia. Circulation. 2011; 124: 00‐00.
Thadani, et al
• Tested maternal and fetal safety – 5 women with pre‐term
pre‐eclampsia• AE: Hypotension that responded to IVF
• Apheresis treatments to prolong pregnancy• 3 women with pre‐term pre‐eclampsia and elevated sFlt‐1
• Goal to prolong pregnancy by 14 days• Targeted 5‐6 L whole blood (1‐1.5 x plasma volume) exchanges
and 25‐35% reduction of sFlt‐1 with each treatment
Thadani, et al. Pilot Study of Extracorpeal Removal of Soluble Fms‐Like Tyrosine Kinase 1
in Preeclampsia. Circulation. 2011; 124: 00‐00.
Thadani, et al• Patient 1: 28 weeks
• 1st
Apheresis tx on Day #4:• sFlt‐1 18,755 13,167 ; Uprot/Cr 4.5 3.4
• 2nd
Apheresis tx on Day #8:• sFlt‐1 18,934 12,475; Uprot/Cr 6.2 3.2
• Delivery on Day 15 (30+0 weeks)• sFlt‐1 25,451; Uprot/Cr 6.1
• Patient 2: 30 weeks (twins)• 1st
Apheresis tx on Day #6:• sFlt‐1 29,068 17,933; Uprot/Cr 1.0 0.55
• 2nd
Aphereis tx on Day #11• sFlt‐1 23,075 15,197; Uprot/Cr 1.9 0.79
• Delivery on Day 19 (32+5 weeks)
Thadani, et al. Pilot Study of Extracorpeal Removal of Soluble Fms‐Like Tyrosine Kinase 1
in Preeclampsia. Circulation. 2011; 124: 00‐00.
Thadani, et al
• Patient 3: 27+4 weeks• Tx on Day 3, 7, 14, 18• Delivered: Day 23, 30+6
weeks
Thadani, et al. Pilot Study of Extracorpeal
Removal of Soluble Fms‐Like Tyrosine Kinase
1 in
Preeclampsia. Circulation. 2011; 124: 00‐00.
Summary• Lupus nephritis is not a contraindication to pregnancy,
although recommend waiting until in remission for a least 6
months to decrease obstetrical risks including HTN and
proteinuria
• Patients with lupus nephritis are at higher risk for preeclampsia, so should be monitored closely by multi‐
disciplinary team throughout their pregnancies
• Monitoring of serum sFlit
levels may become a screening tool
for pre‐eclampsia
in the future (not yet FDA approved for use)
• Currently the only treatment for pre‐eclampsia
is delivery of
the fetus, but apheresis
may prove to be beneficial based on
pilot study
Thank you