lupus nephritis in pregnancy - med.nyu.edu

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



1996; 335: 226‐232.

Trends in Serum Cr



1996; 335: 226‐232.

Renal function 6 months post‐partum



1996; 335: 226‐232.

Outcomes and Neonatal Complications



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.

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• 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

• 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

lupus nephritis in pregnancy - med.nyu.edu

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