Preeclampsia and the Risk of ESRD (Journal Club)

Raj Kiran Medapalli, MD, Raj Kiran Medapalli, MD, MPH.MPH.

Nephrology FellowNephrology Fellow

October 1st, 2008October 1st, 2008

Mount Sinai School of MedicineMount Sinai School of Medicine

Division of NephrologyDivision of NephrologyJournal ClubJournal Club

Preeclampsia and Preeclampsia and the Risk of ESRDthe Risk of ESRD

Vikse et al. Vikse et al.

N Engl J Med. 2008 Aug 21;359(8):800-9.N Engl J Med. 2008 Aug 21;359(8):800-9.

Preeclampsia - Diagnostic Preeclampsia - Diagnostic CriteriaCriteria

SBP ≥ 140 and/or DBP ≥ 90mm Hg SBP ≥ 140 and/or DBP ≥ 90mm Hg that occurs after 20 weeks of that occurs after 20 weeks of gestation in a woman with gestation in a woman with previously normal blood pressure, previously normal blood pressure, andand

Proteinuria, defined as urinary Proteinuria, defined as urinary excretion of 0.3g protein or higher in excretion of 0.3g protein or higher in a 24-hr urine collectiona 24-hr urine collection

Severe PreeclampsiaSevere Preeclampsia New onset proteinuric hypertension and at least New onset proteinuric hypertension and at least

one of the following: one of the following: SBP ≥ 160 or DBP ≥ 110 on two occasions at least 6 SBP ≥ 160 or DBP ≥ 110 on two occasions at least 6

hours aparthours apart Proteinuria ≥ 5g in 24 hoursProteinuria ≥ 5g in 24 hours Oliguria of less than 500ml in 24 hoursOliguria of less than 500ml in 24 hours Cerebral or visual disturbancesCerebral or visual disturbances Pulmonary edema or cyanosisPulmonary edema or cyanosis Epigastric pain or RUQ pain (liver capsule distension)Epigastric pain or RUQ pain (liver capsule distension) Impaired liver function (≥ twice normal Impaired liver function (≥ twice normal

transaminases)transaminases) Thrombocytopenia (< 100, 000)Thrombocytopenia (< 100, 000) Fetal growth restrictionFetal growth restriction

Preeclampsia - IncidencePreeclampsia - Incidence

5-8% of pregnancies in the US5-8% of pregnancies in the US Mild in 75% of the casesMild in 75% of the cases Severe in 25% of the casesSevere in 25% of the cases 10% cases occur in pregnancies less 10% cases occur in pregnancies less

than 34 wks of gestation.than 34 wks of gestation.

References: References: ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Obstet ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Obstet

Gynecol. 2002 Jan;99(1):159-67.Gynecol. 2002 Jan;99(1):159-67. Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: Lessons learned from recent Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: Lessons learned from recent

trials. Am J Obstet Gynecol 2004 Jun;190(6):1520-6.trials. Am J Obstet Gynecol 2004 Jun;190(6):1520-6.

Risk factors for pre-eclampsia at antenatal booking: systematic Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies.review of controlled studies.

Duckitt K and Harrington D. BMJ. 2005 Mar 12;330(7491):565. Duckitt K and Harrington D. BMJ. 2005 Mar 12;330(7491):565.(38 cohort studies published between 1966 and 2002)(38 cohort studies published between 1966 and 2002)

In normal placental development, invasive cytotrophoblasts of fetal origin invade the myometrium and maternal spiral arteries.

During this process the cytotrophoblasts differentiate from an epithelial phenotype to an endothelial phenotype, a process referred to as "pseudovasculogenesis"

End result is transformation of the small-caliber high-resistance spiral arteries into high-caliber capacitance vessels capable of providing placental perfusion adequate to sustain the growing fetus.

Reference: Reference: Karumanchi SA, et al. Preeclampsia: A renal perspective. Kidney Int 2005; 67:2101.Karumanchi SA, et al. Preeclampsia: A renal perspective. Kidney Int 2005; 67:2101.

In preeclampsia, cytotrophoblasts fail to adopt an invasive endothelial phenotype.

And, invasion of the spiral arteries is shallow The end result is that the maternal spiral arteries remain as small

caliber, resistance vessels. This may result in the placental ischemia and possibly release of angiogenic and inflammtory factors into the maternal circulation.

Reference: Reference: Karumanchi SA, et al. Preeclampsia: A renal perspective. Kidney Int 2005; 67:2101.Karumanchi SA, et al. Preeclampsia: A renal perspective. Kidney Int 2005; 67:2101.

Angiogenic ProteinsAngiogenic Proteins Vascular Endothelial Growth Factor (VEGF)Vascular Endothelial Growth Factor (VEGF) is an angiogenic factor is an angiogenic factor

produced by the placenta and it's activities are mainly mediated by produced by the placenta and it's activities are mainly mediated by VEGF Receptor-1 (aka fms-like tyrosine kinase-1 or Flt-1) and VEGF Receptor-1 (aka fms-like tyrosine kinase-1 or Flt-1) and VEGF Receptor - 2 which are selectively expressed on vascular VEGF Receptor - 2 which are selectively expressed on vascular endothelium. endothelium.

Placenta also secretes another angiogenic factor - Placenta also secretes another angiogenic factor - Placental Growth Placental Growth Factor (PlGF)Factor (PlGF) which also binds to VEGF Receptor-1. which also binds to VEGF Receptor-1.

VEGF Receptor-1(Flt-1)VEGF Receptor-1(Flt-1) has two isoforms: a transmembranous has two isoforms: a transmembranous isoform on the vascular endothelium and a isoform on the vascular endothelium and a circulating soluble circulating soluble isoform (sFlt-1).isoform (sFlt-1).

sFlt-1 binds to circulating VEGF and PlGF and prevents their sFlt-1 binds to circulating VEGF and PlGF and prevents their interaction with the transmembranous VEGF Receptor-1 and results interaction with the transmembranous VEGF Receptor-1 and results in endothelial dysfunctionin endothelial dysfunction

VEGF: Vascular Endothelial Growth FactorVEGF: Vascular Endothelial Growth Factor PIGF: Placental Growth FactorPIGF: Placental Growth Factor FLT-1: fms-like Tyrosine Kinase-1 or VEGF Receptor-1FLT-1: fms-like Tyrosine Kinase-1 or VEGF Receptor-1 sFLT-1: soluble circulating isoform of FLT-1sFLT-1: soluble circulating isoform of FLT-1 Reference: Reference: Karumanchi SA, et al. Preeclampsia: A renal perspective. Kidney Int 2005; 67:2101.Karumanchi SA, et al. Preeclampsia: A renal perspective. Kidney Int 2005; 67:2101.

sFlt-1 levels increase during the course of pregnancy in all women. However, compared to normotensive controls, women who went on to develop

preeclampsia began this increase earlier in gestation (at 21 to 24 weeks versus 33 to 36 weeks) and reached higher levels1.

A significant difference in the serum sFlt-1 concentration between the two groups was apparent five weeks before the onset of clinical disease.

Reference: Levine RJ, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Levine RJ, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004 Feb 12;350(7):672-83.Med. 2004 Feb 12;350(7):672-83.

PlGF and VEGF levels fell concurrently with the rise in sFlt-1 (show figure 4), which may have been related, in part, to binding by sFlt-1.

Reference: Levine RJ, et al. Circulating angiogenic factors and the risk of Levine RJ, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004 Feb 12;350(7):672-83.preeclampsia. N Engl J Med. 2004 Feb 12;350(7):672-83.

Endoglin (Eng) is a co-receptor for transforming growth factor (TGF)-beta and is highly expressed on cell membranes of vascular endothelium and syncytiotrophoblasts.

A placenta-derived soluble form of Eng, referred to as soluble endoglin (sEng), is an anti-angiogenic protein that appears to be another important mediator of preeclampsia

sEng inhibits TGF-beta-1 signaling in endothelial cells and blocks TGF-beta-1 mediated vasodilation and promotes hypertension.

Reference: Levine RJ, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Levine RJ, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med. 2006 Sep 7;355(10):992-1005.Engl J Med. 2006 Sep 7;355(10):992-1005.

Suggested Pathophysiology of Suggested Pathophysiology of PreeclampsiaPreeclampsia

Reference: Parikh, SM & Karumanchi, SA. Putting Pressure on Pre-eclampsia. Nat Med 14 (8), 810-812 (2008)

Glomerular EndotheliosisGlomerular Endotheliosis

Swelling of damaged endothelial cells, leads to partial closure of many of the capillary lumens (large arrows). Mitosis within an endothelial cell

(small arrow) is a sign of cellular repair.

Pre-eclampsia and risk of cardiovascular disease and cancer later in life: systematic review and metaanalysis.

Bellamy et al. BMJ 2007;335;974.

In this metaanalyses by Bellamy et In this metaanalyses by Bellamy et al, 25 prospective and retrospective al, 25 prospective and retrospective cohort studies, published between cohort studies, published between 1960 and 2006 were included, 1960 and 2006 were included, providing a dataset of 3,488,160 providing a dataset of 3,488,160 women, with 198,252 affected by women, with 198,252 affected by pre-eclampsia (exposure group) and pre-eclampsia (exposure group) and 29,495 episodes of cardiovascular 29,495 episodes of cardiovascular disease and cancer (study outcomes).disease and cancer (study outcomes).

Preeclampsia and risk of Preeclampsia and risk of HTNHTN

Reference: Bellamy et al. Pre-eclampsia and risk of cardiovascular disease and cancer later in life: systematic review and metaanalysis. BMJ 2007;335;974.

Preeclampsia and risk of Preeclampsia and risk of CVDCVD

Reference: Bellamy et al. Pre-eclampsia and risk of cardiovascular disease and cancer later in life: sytematic review and metaanalysis. BMJ 2007;335;974.

Preeclampsia and risk of Stroke Preeclampsia and risk of Stroke

and DVT.and DVT.

Reference: Bellamy et al. Pre-eclampsia and risk of cardiovascular disease and cancer later in life: sytematic review and metaanalysis. BMJ 2007;335;974.

Long term mortality of mothers and fathers after preeclampsia: population based cohort study. Irgens et al. BMJ. 2001 Nov 24;323(7323):1213-7.

Population based cohort study of registry data.Population based cohort study of registry data. Study Subjects: Study Subjects:

Mothers and fathers of all 626,272 births that were the Mothers and fathers of all 626,272 births that were the mothers' first deliveries, recorded in the mothers' first deliveries, recorded in the Norwegian Norwegian medical birth registrymedical birth registry from 1967 to 1992. from 1967 to 1992.

Parents were divided into 2 cohorts based on whether Parents were divided into 2 cohorts based on whether the mother had pre-eclampsia during the pregnancy.the mother had pre-eclampsia during the pregnancy.

Subjects were also stratified by whether the birth was Subjects were also stratified by whether the birth was pre-term or not, given that pre-eclampsia might be more pre-term or not, given that pre-eclampsia might be more severe in preterm births.severe in preterm births.

Main outcomes: Main outcomes: Total mortality and mortality from cardiovascular Total mortality and mortality from cardiovascular

causes, cancer, and stroke from 1967 to 1992, from data causes, cancer, and stroke from 1967 to 1992, from data from the from the Norwegian registry of causes of deathNorwegian registry of causes of death..

Preeclampsia and long term Preeclampsia and long term mortalitymortality

Reference: Irgens et al. Long term mortality of mothers and fathers after preeclampsia: population based cohort study. BMJ. 2001 Nov 24;323(7323):1213-7.

Preeclampsia and long term Preeclampsia and long term mortalitymortality

Reference: Irgens et al. Long term mortality of mothers and fathers after preeclampsia: population based cohort study. BMJ. 2001 Nov 24;323(7323):1213-7.

Association of maternal endothelial dysfunction with Association of maternal endothelial dysfunction with preeclampsia.preeclampsia.

Chambers et al. JAMA. 2001 Mar 28;285(12):1607-12.Chambers et al. JAMA. 2001 Mar 28;285(12):1607-12.

Design and Setting Design and Setting Case-control study conducted at 3 hospital maternity units Case-control study conducted at 3 hospital maternity units

in London, England, between July 1997 and June 2000.in London, England, between July 1997 and June 2000. Participants Participants

A total of 113 women with previous preeclampsia (n=35 A total of 113 women with previous preeclampsia (n=35 with recurrent episodes; n=78 with a single episode) and with recurrent episodes; n=78 with a single episode) and 48 women with previous uncomplicated pregnancies, all of 48 women with previous uncomplicated pregnancies, all of whom were at least 3 months (median, 3 years) whom were at least 3 months (median, 3 years) postpartum.postpartum.

Main Outcome Measures Main Outcome Measures Brachial artery flow-mediated (endothelium-dependent) Brachial artery flow-mediated (endothelium-dependent)

dilatationdilatation Glyceryl trinitrate–induced (endothelium-independent) Glyceryl trinitrate–induced (endothelium-independent)

dilatationdilatation To investigate oxidative stress, these measurements were To investigate oxidative stress, these measurements were

repeated after administration of ascorbic acid, 1 g repeated after administration of ascorbic acid, 1 g intravenously, in 15 cases and 15 controls.intravenously, in 15 cases and 15 controls.

Persistent Endothelial Dysfunction 5-6 yrs after Persistent Endothelial Dysfunction 5-6 yrs after PreeclampsiaPreeclampsia

Reference: Chambers et al. Association of maternal endothelial dysfunction with preeclampsia. JAMA. 2001 Mar 28;285(12):1607-12.

Microalbuminuria after pregnancy complicaed by preeclampsia.

Bar et al. Nephrol Dial Transplant (1999) 14:1129-1132.

Subjects: Subjects: Study group: 48 women with Study group: 48 women with

preeclampsiapreeclampsia Control group: 44 women with normal Control group: 44 women with normal

pregnancypregnancy Outcomes:Outcomes:

Urinary albumin excretion rate, BP, and Urinary albumin excretion rate, BP, and renal fxn parameters at 2- 4 months and renal fxn parameters at 2- 4 months and 3-5 years post partum.3-5 years post partum.

Persistant microalbuminuria after Persistant microalbuminuria after preeclampsiapreeclampsia

Reference: Bar et al. Microalbuminuria after pregnancy complicaed by preeclampsia. Nephrol Dial Transplant (1999) 14:1129-1132.

Adverse perinatal outcome and later kidney biopsy in the mother. Vikse et al. Am Soc Nephrol. 2006 Mar;17(3):837-45.

All women with a first singleton delivery, All women with a first singleton delivery, registered in the registered in the Medical Birth Registry of Medical Birth Registry of NorwayNorway, from 1967 to 1998 were included., from 1967 to 1998 were included.

Linked to Linked to Norwegian Kidney Biopsy RegistryNorwegian Kidney Biopsy Registry to assess the risk of having a kidney biopsy to assess the risk of having a kidney biopsy later in life. later in life.

Pregnancy-related predictors of later kidney Pregnancy-related predictors of later kidney biopsy were analyzed by Cox regression biopsy were analyzed by Cox regression analyses. analyses.

A total of 756,420 women were included, and A total of 756,420 women were included, and after a mean period of 15.9 ± 9.4 yr, 588 after a mean period of 15.9 ± 9.4 yr, 588 women had a kidney biopsy.women had a kidney biopsy.

Preeclampsia and risk of having a kidney biopsy Preeclampsia and risk of having a kidney biopsy

later in lifelater in life

Reference: Vikse et al. Adverse perinatal outcome and later kidney biopsy in the mother.J Am Soc Nephrol. 2006 Mar;17(3):837-45.

Preeclampsia and risk of having a kidney biopsy Preeclampsia and risk of having a kidney biopsy later in lifelater in life

Reference: Vikse et al. Adverse perinatal outcome and later kidney biopsy in the mother.J Am Soc Nephrol. 2006 Mar;17(3):837-45.

Preeclampsia and Preeclampsia and the Risk of ESRDthe Risk of ESRD

Vikse et al. Vikse et al.

N Engl J Med. 2008 Aug 21;359(8):800-9.N Engl J Med. 2008 Aug 21;359(8):800-9.

Study ObjectivesStudy Objectives

Assess the association between Assess the association between preeclampsia in one or more preeclampsia in one or more pregnancies and subsequent risk of pregnancies and subsequent risk of ESRD.ESRD.

Asses the relationship between Asses the relationship between having a LBW infant or a preterm having a LBW infant or a preterm birth and the risk of later ESRD. birth and the risk of later ESRD.

MethodsMethods Medical Birth Registry of NorwayMedical Birth Registry of Norway

Established 1967Established 1967 Has medical data on all births in Norway with a Has medical data on all births in Norway with a

gestational age ≥ 16 weeks. gestational age ≥ 16 weeks. Notification is compulsory and is done using a form Notification is compulsory and is done using a form

filled out by the attending physician or midwife. filled out by the attending physician or midwife. Includes extensive data on maternal disease and Includes extensive data on maternal disease and

conditions of the new born.conditions of the new born. The diagnosis of preeclampsia have not been directly The diagnosis of preeclampsia have not been directly

validated, but consistency of reported rates has been validated, but consistency of reported rates has been demonstrated among counties and over time. demonstrated among counties and over time.

Validation studies have shown that 97% of pts with a Validation studies have shown that 97% of pts with a diagnosis of DM and 88% of those with rheumatic diagnosis of DM and 88% of those with rheumatic disease are registered with these conditions in the disease are registered with these conditions in the Registry. Registry.

MethodsMethods

Norwegian Renal RegistryNorwegian Renal Registry Established in 1980Established in 1980 Includes data on patients in Norway Includes data on patients in Norway

who have ESRD (defined as need for who have ESRD (defined as need for long term dialysis or renal long term dialysis or renal transplantation), including date of onset transplantation), including date of onset and cause of the disease. and cause of the disease.

National Cause of Death RegistryNational Cause of Death Registry

Study PopulationStudy Population

Inclusion CriteriaInclusion Criteria All women in Norway for whom a first delivery All women in Norway for whom a first delivery

was recorded between 1967 and 1991 in the was recorded between 1967 and 1991 in the Medical Birth Registry of Norway.Medical Birth Registry of Norway.

Data on the first three pregnancies, that Data on the first three pregnancies, that resulted in a live birth or still birth after 16 resulted in a live birth or still birth after 16 wks of gestation were included (through 2004)wks of gestation were included (through 2004)

Exclusion CriteriaExclusion Criteria Women with multiple deliveries.Women with multiple deliveries. Pregnancies occurring after development of Pregnancies occurring after development of

ESRD.ESRD.

Explanatory VariablesExplanatory Variables PreeclampsiaPreeclampsia: 1972 ACOG criteria. : 1972 ACOG criteria.

BP ≥ 140/90 or increase in SBP ≥ 30mm Hg or BP ≥ 140/90 or increase in SBP ≥ 30mm Hg or DBP ≥ 15mm Hg from measurements before 20 DBP ≥ 15mm Hg from measurements before 20 weeks of gestationweeks of gestation

Proteinuria ≥ 0.3g in 24 hrs or urine dipstick ≥ Proteinuria ≥ 0.3g in 24 hrs or urine dipstick ≥ 1+.1+.

Low birth weightLow birth weight: < 2.5 Kg.: < 2.5 Kg. Preterm birthPreterm birth: gestational age < 37 wks.: gestational age < 37 wks. Small for gestational ageSmall for gestational age: below 10 percentile of : below 10 percentile of

sex-specific reference values. sex-specific reference values. DMDM, , HTNHTN, , kidney and urinary tract diseasekidney and urinary tract disease and and

rheumatic diseaserheumatic disease (includes autoimmune connective (includes autoimmune connective tissue disease or inflammatory arthritides).tissue disease or inflammatory arthritides).

Outcome variablesOutcome variables

ESRDESRD: Date of initiation of dialysis : Date of initiation of dialysis or transplantationor transplantation

DeathDeath Follow-up ended December 31, Follow-up ended December 31,

2005. 2005.

Statistical AnalysisStatistical Analysis

Population based retrospective cohort Population based retrospective cohort study.study.

Separate analyses of data from women Separate analyses of data from women with 1 or more, 2 or more and 3 or more with 1 or more, 2 or more and 3 or more pregnancies.pregnancies.

Absolute risk estimates: No. of cases of Absolute risk estimates: No. of cases of ESRD per 100,000 person-yrs of ESRD per 100,000 person-yrs of observation after the observation after the lastlast included included pregnancy. pregnancy.

Statistical AnalysisStatistical Analysis Relative risk estimates using Relative risk estimates using Cox Cox

regression analysesregression analyses.. Model 1Model 1: RR adjusted for year of delivery, : RR adjusted for year of delivery,

maternal age at delivery, maternal marital maternal age at delivery, maternal marital status, still birth, congenital malformation status, still birth, congenital malformation of infant in all included pregnancies. of infant in all included pregnancies.

Model 2Model 2: Pts with DM, HTN, kidney disease : Pts with DM, HTN, kidney disease and rheumatic disease were excluded + RR and rheumatic disease were excluded + RR adjusted for afore mentioned variables. adjusted for afore mentioned variables.

Effects of interaction between preeclampsia Effects of interaction between preeclampsia and LBW or preterm birth was also tested.and LBW or preterm birth was also tested.

Statistical AnalysisStatistical Analysis

Data from mothers who gave birth between Data from mothers who gave birth between 1967 and 1979 were not included in the 1967 and 1979 were not included in the analysis until the occurrence of ESRD could analysis until the occurrence of ESRD could be registered, beginning in 1980, when the be registered, beginning in 1980, when the Norwegian Renal Registry was started. Norwegian Renal Registry was started.

““For example, A mother with her For example, A mother with her lastlast delivery in 1973 would be included in the delivery in 1973 would be included in the analyses 7yrs after the delivery(from 1980 analyses 7yrs after the delivery(from 1980 onwards), and her data would be censored onwards), and her data would be censored 32 yrs after the delivery if she did not have 32 yrs after the delivery if she did not have ESRD” (follow-up ended in 2005)ESRD” (follow-up ended in 2005)

1980197319701967 2005P#1

P#2

3 yrs 7 yrs 25 yrs

1980197319701967 1990 2005P#1

P#2 ESRD/Death

3 yrs 7 yrs 10 yrs

Example 1 : No ESRD or Death during the study period (1967 to 2005)

Total Time included in the study = 7 + 25 = 32 years

Example 2: ESRD or Death in 1990

Total time included in the study: 7 + 10 = 17 years

1980197319701967 2005P#1

P#2

1980197319701967 1976 2005P#1

P#2 Death

Example 3 : ESRD in 1976

Total Time included in the study =???It is not clear if this patient would be registered in the Renal Registry or not.

Example 4: Death in 1976

Total time included in the study: ???Authors did not specify in the methods section how they dealt with these pts

1976ESRD

ResultsResults Total of 570, 433 women. 480, 006 had a second child. 210, Total of 570, 433 women. 480, 006 had a second child. 210,

660 had a third child.660 had a third child. Mean duration of follow-up: 26.5 ± 7.5, 22.8 ± 8 and 18.7 ± Mean duration of follow-up: 26.5 ± 7.5, 22.8 ± 8 and 18.7 ±

8.2 yrs after 1st, 2nd and 3rd pregnancies, respectively. 8.2 yrs after 1st, 2nd and 3rd pregnancies, respectively. ESRD developed in 477 womenESRD developed in 477 women

Overall rate after first birth: 3.7 per 100,000 women per year.Overall rate after first birth: 3.7 per 100,000 women per year. Mean age @ onset of ESRD: 41 ± 10 yrs Mean age @ onset of ESRD: 41 ± 10 yrs Mean duration of onset of ESRD after 1st pregnancy: 17 ± 9 Mean duration of onset of ESRD after 1st pregnancy: 17 ± 9

yrs. yrs. Absolute risk: Absolute risk:

0.007% after 5 years0.007% after 5 years 0.015% after 10 yrs0.015% after 10 yrs 0.051% after 20 yrs0.051% after 20 yrs 0.10% after 30 yrs0.10% after 30 yrs 0.18% after 38 yrs0.18% after 38 yrs

Cumulative risk of ESRDCumulative risk of ESRD

Etiology of ESRD in the Etiology of ESRD in the StudyStudy

Out of the 477 cases of ESRD:Out of the 477 cases of ESRD: 168 - Glomerulonephritis168 - Glomerulonephritis 100 - Hereditary or congenital causes 100 - Hereditary or congenital causes

84 had ADPCKD84 had ADPCKD 68 - Diabetic nephropathy68 - Diabetic nephropathy 82 - Other causes82 - Other causes 59 - Interstitial nephritis59 - Interstitial nephritis

Preeclampsia was associated with similar Preeclampsia was associated with similar relative risk for development of ESRD due relative risk for development of ESRD due to a specific cause and for development of to a specific cause and for development of ESRD in general. ESRD in general.

Summary of resultsSummary of results Risk of development of ESRD among women Risk of development of ESRD among women

with a history of previous preeclampsia was with a history of previous preeclampsia was more than 3 times higher than risk among more than 3 times higher than risk among women without preeclampsia.women without preeclampsia.

Results were significant even after Results were significant even after adjustment for potential birth related adjustment for potential birth related confounders and exclusion of women who had confounders and exclusion of women who had a diagnosis of DM, HTN, kidney disease or a diagnosis of DM, HTN, kidney disease or rheumatic disease before their pregnancy. rheumatic disease before their pregnancy.

However absolute risk is very low, even is However absolute risk is very low, even is women who had multiple episodes of women who had multiple episodes of preeclampsia.preeclampsia.

Summary of resultsSummary of results Association was stronger if the Association was stronger if the

preeclamptic pregnancy resulted in a LBW preeclamptic pregnancy resulted in a LBW or preterm infant.or preterm infant. This suggests that severity of pre-eclampsia This suggests that severity of pre-eclampsia

may be a marker for future ESRD risk. may be a marker for future ESRD risk.

LBW or pre-term infant was a risk marker LBW or pre-term infant was a risk marker for ESRD, even in women who did not have for ESRD, even in women who did not have preeclampsia.preeclampsia. This suggests that placental dysfunction, even This suggests that placental dysfunction, even

in the absence of preeclampsia, maybe a in the absence of preeclampsia, maybe a marker for future ESRD risk. marker for future ESRD risk.

Summary of resultsSummary of results

The risk of ESRD was greater in women The risk of ESRD was greater in women with more than one preeclamptic with more than one preeclamptic pregnancy than in those with only one pregnancy than in those with only one such pregnancy (“dose-response” effect).such pregnancy (“dose-response” effect).

Among women who had preeclampsia in Among women who had preeclampsia in only one of their pregnancies, the risk of only one of their pregnancies, the risk of ESRD was greater if preeclampsia ESRD was greater if preeclampsia occurred during the last pregnancy. occurred during the last pregnancy. (maternal age?, more severe dz?) (maternal age?, more severe dz?)

Strengths of the studyStrengths of the study

Use of linked data from large Use of linked data from large national registries spanning over national registries spanning over four decades. four decades.

Weaknesses of the studyWeaknesses of the study Accuracy of coding of preeclampsia in the Registry was not Accuracy of coding of preeclampsia in the Registry was not

validated (However random misclassification would bias the validated (However random misclassification would bias the results towards the null).results towards the null).

Accuracy of coding for diabetes was validated to be 98%, but for Accuracy of coding for diabetes was validated to be 98%, but for rheumatic disease it was only 88% and no validation studies were rheumatic disease it was only 88% and no validation studies were available to confirm accuracy of coding of HTN and kidney disease available to confirm accuracy of coding of HTN and kidney disease variables or BP and urinary dipstick measurement. (However, variables or BP and urinary dipstick measurement. (However, similar results after exclusion of women with these diagnoses). similar results after exclusion of women with these diagnoses).

Outcomes before 1980 were not registered and it is not clear how Outcomes before 1980 were not registered and it is not clear how the patients who died before 1980 were dealt with. Depending on the patients who died before 1980 were dealt with. Depending on the incidence of ESRD and rates of mortality in the pre-eclampsia the incidence of ESRD and rates of mortality in the pre-eclampsia and non-preeclampsia groups, this could bias the results either and non-preeclampsia groups, this could bias the results either way.way.

Information not available on BMI/Obesity - a recognized risk factor Information not available on BMI/Obesity - a recognized risk factor for both preeclampsia and ESRD (but, wouldn’t account for the for both preeclampsia and ESRD (but, wouldn’t account for the entire magnitude of association).entire magnitude of association).

Information on missing data unavailable. Information on missing data unavailable.

Plausible explanations Plausible explanations for the observed for the observed

associationassociation Presence of underlying risk factors which predispose to Presence of underlying risk factors which predispose to both preeclampsia and ESRD.both preeclampsia and ESRD.

Obesity, HTN, insulin resistance and endothelial Obesity, HTN, insulin resistance and endothelial dysfunction have been linked to both diseasesdysfunction have been linked to both diseases1,21,2..

Other observational studies done in early or mid Other observational studies done in early or mid pregnancy have shown that women in whom pregnancy have shown that women in whom preeclampsia subsequently developed had higher BP preeclampsia subsequently developed had higher BP (even within normal range), higher insulin levels and (even within normal range), higher insulin levels and higher cholesterol levels than women who remained higher cholesterol levels than women who remained normotensive ,suggesting that factors pre-disposing to normotensive ,suggesting that factors pre-disposing to kidney disease antedated the preeclampsiakidney disease antedated the preeclampsia33..

References:References:1.1. Sibai et al. Risk factors for preeclampsia in healthy nulliparous women: a prospective Sibai et al. Risk factors for preeclampsia in healthy nulliparous women: a prospective

multicenter study. AM J Obstet Gynecol 1995;172:642-8.multicenter study. AM J Obstet Gynecol 1995;172:642-8.2.2. de Jong et al. From secondary to primary prevention of progressive renal disease: the de Jong et al. From secondary to primary prevention of progressive renal disease: the

case for screenign for albuminuria. Kidney Int 2004;66:2109-18.case for screenign for albuminuria. Kidney Int 2004;66:2109-18.3.3. Seely at al. Insulin resistance and it’s potential role in pregnancy induced Seely at al. Insulin resistance and it’s potential role in pregnancy induced

hypertension. J Clin Endocrinol Metab 2003;88:2393-8.hypertension. J Clin Endocrinol Metab 2003;88:2393-8.

Plausible explanationsPlausible explanations

Preeclampsia may exacerbate subclinical Preeclampsia may exacerbate subclinical kidney disease leading to ESRD later in kidney disease leading to ESRD later in life.life.

A study involving postpartum renal biopsies of A study involving postpartum renal biopsies of women who had severe preeclampsia found women who had severe preeclampsia found previously unrecognized renal disease in more previously unrecognized renal disease in more than 1 in 10 women, most frequently in those than 1 in 10 women, most frequently in those women with early onset of preeclampsia women with early onset of preeclampsia (before 30 weeks of gestation)(before 30 weeks of gestation)11..

Reference:Reference:

1.1. Murakami et al. Renal disease in women with severe preeclampsia or gestational Murakami et al. Renal disease in women with severe preeclampsia or gestational proteinuria. Obstet Gynecol 2000;96:945-9.proteinuria. Obstet Gynecol 2000;96:945-9.

Plausible explanationsPlausible explanations Preeclampsia may lead to ESRD later in Preeclampsia may lead to ESRD later in

life in some women. life in some women. Other observational studies have found that Other observational studies have found that

20-40% of women with pre-eclampsia have 20-40% of women with pre-eclampsia have microabuminuria 3-5 yrs after pregnancy, as microabuminuria 3-5 yrs after pregnancy, as compared with only 2% of women without compared with only 2% of women without preeclampsiapreeclampsia1,21,2. .

References: References: 1.1. Bar et al. Microalbuminuria after pregnancy complicated by pre-eclampsia. Bar et al. Microalbuminuria after pregnancy complicated by pre-eclampsia.

Neprol Dial Transplant 1999;14:1129-32. Neprol Dial Transplant 1999;14:1129-32.

2.2. Nisell et al. Blood pressure and renal function seven years after pregnancy Nisell et al. Blood pressure and renal function seven years after pregnancy

compicated by hypertension. Br J Obstet Gynaecol 1995;102:876-81.compicated by hypertension. Br J Obstet Gynaecol 1995;102:876-81.

ConclusionsConclusions

Pre-eclampsia appears to be a clinical Pre-eclampsia appears to be a clinical marker for an increased risk of HTN, marker for an increased risk of HTN, endothelial dysfunction, CVD and endothelial dysfunction, CVD and possibly ESRD later in life (although possibly ESRD later in life (although the absolute risk is very low). the absolute risk is very low).

Further research is needed to better Further research is needed to better understand the underlying understand the underlying mechanisms and to guide clinical mechanisms and to guide clinical follow-up of women with history of follow-up of women with history of pre-eclampsia. pre-eclampsia.