Raj Kiran Medapalli, MD, MPH. Nephrology Fellow October 1st, 2008 Mount Sinai School of Medicine Division of Nephrology Jo...
Preeclampsia and the Risk of ESRD Vikse et al.  N Engl J Med. 2008 Aug 21;359(8):800-9.
Preeclampsia - Diagnostic Criteria <ul><li>SBP ≥ 140 and/or DBP ≥  90mm Hg that occurs after 20 weeks of gestation in a wo...
Severe Preeclampsia <ul><li>New onset proteinuric hypertension and at least one of the following:  </li></ul><ul><ul><li>S...
Preeclampsia - Incidence <ul><li>5-8% of pregnancies in the US </li></ul><ul><ul><li>Mild in 75% of the cases </li></ul></...
Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies.  Duckitt K and Harrington D....
<ul><li>In normal placental development, invasive cytotrophoblasts of fetal origin invade the myometrium and maternal spir...
<ul><li>In preeclampsia, cytotrophoblasts fail to adopt an invasive endothelial phenotype.  </li></ul><ul><li>And, invasio...
Angiogenic Proteins <ul><li>Vascular Endothelial Growth Factor (VEGF)  is an angiogenic factor produced by the placenta an...
<ul><li>VEGF: Vascular Endothelial Growth Factor </li></ul><ul><li>PIGF: Placental Growth Factor </li></ul><ul><li>FLT-1: ...
<ul><li>sFlt-1 levels increase during the course of pregnancy in all women.  </li></ul><ul><li>However, compared to normot...
<ul><li>PlGF and VEGF levels fell concurrently with the rise in sFlt-1 (show figure 4), which may have been related, in pa...
<ul><li>Endoglin (Eng)   is a co-receptor for transforming growth factor (TGF)-beta and is highly expressed on cell membra...
Suggested Pathophysiology of Preeclampsia Reference:  Parikh, SM & Karumanchi, SA. Putting Pressure on Pre-eclampsia.  Nat...
Glomerular Endotheliosis Swelling of damaged endothelial cells, leads to partial closure of many of  the capillary lumens ...
Pre-eclampsia and risk of cardiovascular disease and cancer later in life: systematic review and metaanalysis.  Bellamy et...
Preeclampsia and risk of HTN Reference: Bellamy et al. Pre-eclampsia and risk of cardiovascular disease and cancer later i...
Preeclampsia and risk of CVD Reference: Bellamy et al. Pre-eclampsia and risk of cardiovascular disease and cancer later i...
Preeclampsia and risk of Stroke and DVT.   Reference: Bellamy et al. Pre-eclampsia and risk of cardiovascular disease and ...
Long term mortality of mothers and fathers after preeclampsia: population based cohort study.   Irgens et al.  BMJ. 2001 N...
Preeclampsia and long term mortality Reference: Irgens et al. Long term mortality of mothers and fathers after preeclampsi...
Preeclampsia and long term mortality Reference: Irgens et al. Long term mortality of mothers and fathers after preeclampsi...
Association of maternal endothelial dysfunction with preeclampsia. Chambers et al. JAMA. 2001 Mar 28;285(12):1607-12. <ul>...
Persistent Endothelial Dysfunction 5-6 yrs after Preeclampsia Reference:  Chambers et al. Association of maternal endothel...
Microalbuminuria after pregnancy complicaed by preeclampsia.   Bar et al. Nephrol Dial Transplant (1999) 14:1129-1132. <ul...
Persistant microalbuminuria after preeclampsia Reference: Bar et al. Microalbuminuria after pregnancy complicaed by preecl...
Adverse perinatal outcome and later kidney biopsy in the mother.  Vikse et al. Am Soc Nephrol. 2006 Mar;17(3):837-45. <ul>...
Preeclampsia and risk of having a kidney biopsy later in life   Reference:  Vikse et al. Adverse perinatal outcome and lat...
Preeclampsia and risk of having a kidney biopsy later in life Reference:  Vikse et al. Adverse perinatal outcome and later...
Preeclampsia and the Risk of ESRD Vikse et al.  N Engl J Med. 2008 Aug 21;359(8):800-9.
Study Objectives <ul><li>Assess the association between preeclampsia in one or more pregnancies and subsequent risk of ESR...
Methods <ul><li>Medical Birth Registry of Norway </li></ul><ul><ul><li>Established 1967 </li></ul></ul><ul><ul><li>Has med...
Methods <ul><li>Norwegian Renal Registry </li></ul><ul><ul><li>Established in 1980 </li></ul></ul><ul><ul><li>Includes dat...
Study Population <ul><li>Inclusion Criteria </li></ul><ul><ul><li>All women in Norway for whom a first delivery was record...
Explanatory Variables <ul><li>Preeclampsia : 1972 ACOG criteria.  </li></ul><ul><ul><li>BP ≥ 140/90 or increase in SBP ≥ 3...
Outcome variables <ul><li>ESRD : Date of initiation of dialysis or transplantation </li></ul><ul><li>Death   </li></ul><ul...
Statistical Analysis <ul><li>Population based retrospective cohort study. </li></ul><ul><li>Separate analyses of data from...
Statistical Analysis <ul><li>Relative risk estimates using  Cox regression analyses . </li></ul><ul><li>Model 1 : RR adjus...
Statistical Analysis <ul><li>Data from mothers who gave birth between 1967 and 1979 were not included in the analysis unti...
1980 1973 1970 1967 2005 P#1 P#2 3 yrs 7 yrs 25 yrs 1980 1973 1970 1967 1990 2005 P#1 P#2 ESRD/Death 3 yrs 7 yrs 10 yrs Ex...
1980 1973 1970 1967 2005 P#1 P#2 1980 1973 1970 1967 1976 2005 P#1 P#2 Death Example 3 : ESRD in 1976 Total Time included ...
 
Results <ul><li>Total of 570, 433 women. 480, 006 had a second child. 210, 660 had a third child. </li></ul><ul><li>Mean d...
 
Cumulative risk of ESRD
 
 
 
Etiology of ESRD in the Study <ul><li>Out of the 477 cases of ESRD: </li></ul><ul><ul><li>168 - Glomerulonephritis </li></...
Summary of results <ul><li>Risk of development of ESRD among women with a history of previous preeclampsia was more than 3...
Summary of results <ul><li>Association was stronger if the preeclamptic pregnancy resulted in a LBW or preterm infant. </l...
Summary of results <ul><li>The risk of ESRD was greater in women with more than one preeclamptic pregnancy than in those w...
Strengths of the study <ul><li>Use of linked data from large national registries spanning over four decades.  </li></ul>
Weaknesses of the study <ul><li>Accuracy of coding of preeclampsia in the Registry was not validated (However random miscl...
Plausible explanations for the observed association <ul><li>Presence of underlying risk factors which predispose to both p...
Plausible explanations <ul><li>Preeclampsia may exacerbate subclinical kidney disease leading to ESRD later in life. </li>...
Plausible explanations <ul><li>Preeclampsia may lead to ESRD later in life in some women.  </li></ul><ul><ul><li>Other obs...
Conclusions <ul><li>Pre-eclampsia appears to be a clinical marker for an increased risk of HTN, endothelial dysfunction, C...
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Preeclampsia and the Risk of ESRD (Journal Club)

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  • I-squared, is a measure of heterogeneity among individual studies that cannot be explained by chance. It ranges between 0% and 100% with lower values representing less heterogeneity, with values of 25%, 50%, and 75% representing low, moderate, and high heterogeneity.
  • In this metanalyses by Bellamy et al, 25 prospective and retrospective cohort studies, published between 1960 and 2006 were included, providing a dataset of 3,488,160 women, with 198,252 affected by pre-eclampsia (exposure group) and 29,495 episodes of cardiovascular disease and cancer (study outcomes).
  • Preeclampsia and the Risk of ESRD (Journal Club)

    1. 1. Raj Kiran Medapalli, MD, MPH. Nephrology Fellow October 1st, 2008 Mount Sinai School of Medicine Division of Nephrology Journal Club
    2. 2. Preeclampsia and the Risk of ESRD Vikse et al. N Engl J Med. 2008 Aug 21;359(8):800-9.
    3. 3. Preeclampsia - Diagnostic Criteria <ul><li>SBP ≥ 140 and/or DBP ≥ 90mm Hg that occurs after 20 weeks of gestation in a woman with previously normal blood pressure, and </li></ul><ul><li>Proteinuria, defined as urinary excretion of 0.3g protein or higher in a 24-hr urine collection </li></ul>
    4. 4. Severe Preeclampsia <ul><li>New onset proteinuric hypertension and at least one of the following: </li></ul><ul><ul><li>SBP ≥ 160 or DBP ≥ 110 on two occasions at least 6 hours apart </li></ul></ul><ul><ul><li>Proteinuria ≥ 5g in 24 hours </li></ul></ul><ul><ul><li>Oliguria of less than 500ml in 24 hours </li></ul></ul><ul><ul><li>Cerebral or visual disturbances </li></ul></ul><ul><ul><li>Pulmonary edema or cyanosis </li></ul></ul><ul><ul><li>Epigastric pain or RUQ pain (liver capsule distension) </li></ul></ul><ul><ul><li>Impaired liver function (≥ twice normal transaminases) </li></ul></ul><ul><ul><li>Thrombocytopenia (< 100, 000) </li></ul></ul><ul><ul><li>Fetal growth restriction </li></ul></ul>
    5. 5. Preeclampsia - Incidence <ul><li>5-8% of pregnancies in the US </li></ul><ul><ul><li>Mild in 75% of the cases </li></ul></ul><ul><ul><li>Severe in 25% of the cases </li></ul></ul><ul><ul><li>10% cases occur in pregnancies less than 34 wks of gestation. </li></ul></ul><ul><li>References: </li></ul><ul><ul><li>ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol. 2002 Jan;99(1):159-67. </li></ul></ul><ul><ul><li>Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: Lessons learned from recent trials. Am J Obstet Gynecol 2004 Jun;190(6):1520-6. </li></ul></ul>
    6. 6. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. Duckitt K and Harrington D. BMJ. 2005 Mar 12;330(7491):565. (38 cohort studies published between 1966 and 2002)
    7. 7. <ul><li>In normal placental development, invasive cytotrophoblasts of fetal origin invade the myometrium and maternal spiral arteries. </li></ul><ul><li>During this process the cytotrophoblasts differentiate from an epithelial phenotype to an endothelial phenotype, a process referred to as &quot; pseudovasculogenesis &quot; </li></ul><ul><li>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. </li></ul><ul><li>Reference: Karumanchi SA, et al. Preeclampsia: A renal perspective. Kidney Int 2005; 67:2101. </li></ul>
    8. 8. <ul><li>In preeclampsia, cytotrophoblasts fail to adopt an invasive endothelial phenotype. </li></ul><ul><li>And, invasion of the spiral arteries is shallow </li></ul><ul><li>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. </li></ul><ul><li>Reference: Karumanchi SA, et al. Preeclampsia: A renal perspective. Kidney Int 2005; 67:2101. </li></ul>
    9. 9. Angiogenic Proteins <ul><li>Vascular Endothelial Growth Factor (VEGF) is an angiogenic factor 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 - 2 which are selectively expressed on vascular endothelium. </li></ul><ul><li>Placenta also secretes another angiogenic factor - Placental Growth Factor (PlGF) which also binds to VEGF Receptor-1. </li></ul><ul><li>VEGF Receptor-1(Flt-1) has two isoforms: a transmembranous isoform on the vascular endothelium and a circulating soluble isoform (sFlt-1). </li></ul><ul><li>sFlt-1 binds to circulating VEGF and PlGF and prevents their interaction with the transmembranous VEGF Receptor-1 and results in endothelial dysfunction </li></ul>
    10. 10. <ul><li>VEGF: Vascular Endothelial Growth Factor </li></ul><ul><li>PIGF: Placental Growth Factor </li></ul><ul><li>FLT-1: fms-like Tyrosine Kinase-1 or VEGF Receptor-1 </li></ul><ul><li>sFLT-1: soluble circulating isoform of FLT-1 </li></ul><ul><li>Reference: Karumanchi SA, et al. Preeclampsia: A renal perspective. Kidney Int 2005; 67:2101. </li></ul>
    11. 11. <ul><li>sFlt-1 levels increase during the course of pregnancy in all women. </li></ul><ul><li>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 levels 1 . </li></ul><ul><li>A significant difference in the serum sFlt-1 concentration between the two groups was apparent five weeks before the onset of clinical disease. </li></ul><ul><li>Reference: Levine RJ, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004 Feb 12;350(7):672-83. </li></ul>
    12. 12. <ul><li>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. </li></ul><ul><li>Reference: Levine RJ, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004 Feb 12;350(7):672-83. </li></ul>
    13. 13. <ul><li>Endoglin (Eng) is a co-receptor for transforming growth factor (TGF)-beta and is highly expressed on cell membranes of vascular endothelium and syncytiotrophoblasts. </li></ul><ul><li>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 </li></ul><ul><li>sEng inhibits TGF-beta-1 signaling in endothelial cells and blocks TGF-beta-1 mediated vasodilation and promotes hypertension. </li></ul><ul><li>Reference: Levine RJ, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med. 2006 Sep 7;355(10):992-1005. </li></ul>
    14. 14. Suggested Pathophysiology of Preeclampsia Reference: Parikh, SM & Karumanchi, SA. Putting Pressure on Pre-eclampsia. Nat Med 14 (8), 810-812 (2008)
    15. 15. Glomerular 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.
    16. 16. Pre-eclampsia and risk of cardiovascular disease and cancer later in life: systematic review and metaanalysis. Bellamy et al. BMJ 2007;335;974. <ul><li>In this metaanalyses by Bellamy et al, 25 prospective and retrospective cohort studies, published between 1960 and 2006 were included, providing a dataset of 3,488,160 women, with 198,252 affected by pre-eclampsia (exposure group) and 29,495 episodes of cardiovascular disease and cancer (study outcomes). </li></ul>
    17. 17. Preeclampsia and risk of HTN Reference: Bellamy et al. Pre-eclampsia and risk of cardiovascular disease and cancer later in life: systematic review and metaanalysis. BMJ 2007;335;974.
    18. 18. Preeclampsia and risk of CVD Reference: Bellamy et al. Pre-eclampsia and risk of cardiovascular disease and cancer later in life: sytematic review and metaanalysis. BMJ 2007;335;974.
    19. 19. Preeclampsia and risk of Stroke 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.
    20. 20. Long term mortality of mothers and fathers after preeclampsia: population based cohort study. Irgens et al. BMJ. 2001 Nov 24;323(7323):1213-7 . <ul><li>Population based cohort study of registry data. </li></ul><ul><li>Study Subjects: </li></ul><ul><ul><li>Mothers and fathers of all 626,272 births that were the mothers' first deliveries, recorded in the Norwegian medical birth registry from 1967 to 1992. </li></ul></ul><ul><ul><li>Parents were divided into 2 cohorts based on whether the mother had pre-eclampsia during the pregnancy. </li></ul></ul><ul><ul><li>Subjects were also stratified by whether the birth was pre-term or not, given that pre-eclampsia might be more severe in preterm births. </li></ul></ul><ul><li>Main outcomes: </li></ul><ul><ul><li>Total mortality and mortality from cardiovascular causes, cancer, and stroke from 1967 to 1992, from data from the Norwegian registry of causes of death . </li></ul></ul>
    21. 21. Preeclampsia and long term mortality 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 .
    22. 22. Preeclampsia and long term mortality 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 .
    23. 23. Association of maternal endothelial dysfunction with preeclampsia. Chambers et al. JAMA. 2001 Mar 28;285(12):1607-12. <ul><li>Design and Setting </li></ul><ul><ul><li>Case-control study conducted at 3 hospital maternity units in London, England, between July 1997 and June 2000. </li></ul></ul><ul><li>Participants </li></ul><ul><ul><li>A total of 113 women with previous preeclampsia (n=35 with recurrent episodes; n=78 with a single episode) and 48 women with previous uncomplicated pregnancies, all of whom were at least 3 months (median, 3 years) postpartum. </li></ul></ul><ul><li>Main Outcome Measures </li></ul><ul><ul><li>Brachial artery flow-mediated (endothelium-dependent) dilatation </li></ul></ul><ul><ul><li>Glyceryl trinitrate–induced (endothelium-independent) dilatation </li></ul></ul><ul><ul><li>To investigate oxidative stress, these measurements were repeated after administration of ascorbic acid, 1 g intravenously, in 15 cases and 15 controls. </li></ul></ul>
    24. 24. Persistent Endothelial Dysfunction 5-6 yrs after Preeclampsia Reference: Chambers et al. Association of maternal endothelial dysfunction with preeclampsia. JAMA. 2001 Mar 28;285(12):1607-12.
    25. 25. Microalbuminuria after pregnancy complicaed by preeclampsia. Bar et al. Nephrol Dial Transplant (1999) 14:1129-1132. <ul><li>Subjects: </li></ul><ul><ul><li>Study group: 48 women with preeclampsia </li></ul></ul><ul><ul><li>Control group: 44 women with normal pregnancy </li></ul></ul><ul><li>Outcomes: </li></ul><ul><ul><li>Urinary albumin excretion rate, BP, and renal fxn parameters at 2- 4 months and 3-5 years post partum. </li></ul></ul>
    26. 26. Persistant microalbuminuria after preeclampsia Reference: Bar et al. Microalbuminuria after pregnancy complicaed by preeclampsia. Nephrol Dial Transplant (1999) 14:1129-1132.
    27. 27. Adverse perinatal outcome and later kidney biopsy in the mother. Vikse et al. Am Soc Nephrol. 2006 Mar;17(3):837-45. <ul><li>All women with a first singleton delivery, registered in the Medical Birth Registry of Norway , from 1967 to 1998 were included. </li></ul><ul><li>Linked to Norwegian Kidney Biopsy Registry to assess the risk of having a kidney biopsy later in life. </li></ul><ul><li>Pregnancy-related predictors of later kidney biopsy were analyzed by Cox regression analyses. </li></ul><ul><li>A total of 756,420 women were included, and after a mean period of 15.9 ± 9.4 yr, 588 women had a kidney biopsy. </li></ul>
    28. 28. Preeclampsia and risk of having a kidney biopsy later 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.
    29. 29. Preeclampsia and risk of having a kidney biopsy later 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.
    30. 30. Preeclampsia and the Risk of ESRD Vikse et al. N Engl J Med. 2008 Aug 21;359(8):800-9.
    31. 31. Study Objectives <ul><li>Assess the association between preeclampsia in one or more pregnancies and subsequent risk of ESRD. </li></ul><ul><li>Asses the relationship between having a LBW infant or a preterm birth and the risk of later ESRD. </li></ul>
    32. 32. Methods <ul><li>Medical Birth Registry of Norway </li></ul><ul><ul><li>Established 1967 </li></ul></ul><ul><ul><li>Has medical data on all births in Norway with a gestational age ≥ 16 weeks. </li></ul></ul><ul><ul><li>Notification is compulsory and is done using a form filled out by the attending physician or midwife. </li></ul></ul><ul><ul><li>Includes extensive data on maternal disease and conditions of the new born. </li></ul></ul><ul><ul><li>The diagnosis of preeclampsia have not been directly validated, but consistency of reported rates has been demonstrated among counties and over time. </li></ul></ul><ul><ul><li>Validation studies have shown that 97% of pts with a diagnosis of DM and 88% of those with rheumatic disease are registered with these conditions in the Registry. </li></ul></ul>
    33. 33. Methods <ul><li>Norwegian Renal Registry </li></ul><ul><ul><li>Established in 1980 </li></ul></ul><ul><ul><li>Includes data on patients in Norway who have ESRD (defined as need for long term dialysis or renal transplantation), including date of onset and cause of the disease. </li></ul></ul><ul><li>National Cause of Death Registry </li></ul>
    34. 34. Study Population <ul><li>Inclusion Criteria </li></ul><ul><ul><li>All women in Norway for whom a first delivery was recorded between 1967 and 1991 in the Medical Birth Registry of Norway. </li></ul></ul><ul><ul><li>Data on the first three pregnancies, that resulted in a live birth or still birth after 16 wks of gestation were included (through 2004) </li></ul></ul><ul><li>Exclusion Criteria </li></ul><ul><ul><li>Women with multiple deliveries. </li></ul></ul><ul><ul><li>Pregnancies occurring after development of ESRD. </li></ul></ul>
    35. 35. Explanatory Variables <ul><li>Preeclampsia : 1972 ACOG criteria. </li></ul><ul><ul><li>BP ≥ 140/90 or increase in SBP ≥ 30mm Hg or DBP ≥ 15mm Hg from measurements before 20 weeks of gestation </li></ul></ul><ul><ul><li>Proteinuria ≥ 0.3g in 24 hrs or urine dipstick ≥ 1+. </li></ul></ul><ul><li>Low birth weight : < 2.5 Kg. </li></ul><ul><li>Preterm birth : gestational age < 37 wks. </li></ul><ul><li>Small for gestational age : below 10 percentile of sex-specific reference values. </li></ul><ul><li>DM , HTN , kidney and urinary tract disease and rheumatic disease (includes autoimmune connective tissue disease or inflammatory arthritides). </li></ul>
    36. 36. Outcome variables <ul><li>ESRD : Date of initiation of dialysis or transplantation </li></ul><ul><li>Death </li></ul><ul><li>Follow-up ended December 31, 2005. </li></ul>
    37. 37. Statistical Analysis <ul><li>Population based retrospective cohort study. </li></ul><ul><li>Separate analyses of data from women with 1 or more, 2 or more and 3 or more pregnancies. </li></ul><ul><li>Absolute risk estimates: No. of cases of ESRD per 100,000 person-yrs of observation after the last included pregnancy. </li></ul>
    38. 38. Statistical Analysis <ul><li>Relative risk estimates using Cox regression analyses . </li></ul><ul><li>Model 1 : RR adjusted for year of delivery, maternal age at delivery, maternal marital status, still birth, congenital malformation of infant in all included pregnancies. </li></ul><ul><li>Model 2 : Pts with DM, HTN, kidney disease and rheumatic disease were excluded + RR adjusted for afore mentioned variables. </li></ul><ul><li>Effects of interaction between preeclampsia and LBW or preterm birth was also tested. </li></ul>
    39. 39. Statistical Analysis <ul><li>Data from mothers who gave birth between 1967 and 1979 were not included in the analysis until the occurrence of ESRD could be registered, beginning in 1980, when the Norwegian Renal Registry was started. </li></ul><ul><li>“ For example, A mother with her last delivery in 1973 would be included in the analyses 7yrs after the delivery(from 1980 onwards), and her data would be censored 32 yrs after the delivery if she did not have ESRD” (follow-up ended in 2005) </li></ul>
    40. 40. 1980 1973 1970 1967 2005 P#1 P#2 3 yrs 7 yrs 25 yrs 1980 1973 1970 1967 1990 2005 P#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
    41. 41. 1980 1973 1970 1967 2005 P#1 P#2 1980 1973 1970 1967 1976 2005 P#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 1976 ESRD
    42. 43. Results <ul><li>Total of 570, 433 women. 480, 006 had a second child. 210, 660 had a third child. </li></ul><ul><li>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. </li></ul><ul><li>ESRD developed in 477 women </li></ul><ul><ul><li>Overall rate after first birth: 3.7 per 100,000 women per year. </li></ul></ul><ul><ul><li>Mean age @ onset of ESRD: 41 ± 10 yrs </li></ul></ul><ul><ul><li>Mean duration of onset of ESRD after 1st pregnancy: 17 ± 9 yrs. </li></ul></ul><ul><li>Absolute risk: </li></ul><ul><ul><li>0.007% after 5 years </li></ul></ul><ul><ul><li>0.015% after 10 yrs </li></ul></ul><ul><ul><li>0.051% after 20 yrs </li></ul></ul><ul><ul><li>0.10% after 30 yrs </li></ul></ul><ul><ul><li>0.18% after 38 yrs </li></ul></ul>
    43. 45. Cumulative risk of ESRD
    44. 49. Etiology of ESRD in the Study <ul><li>Out of the 477 cases of ESRD: </li></ul><ul><ul><li>168 - Glomerulonephritis </li></ul></ul><ul><ul><li>100 - Hereditary or congenital causes </li></ul></ul><ul><ul><ul><li>84 had ADPCKD </li></ul></ul></ul><ul><ul><li>68 - Diabetic nephropathy </li></ul></ul><ul><ul><li>82 - Other causes </li></ul></ul><ul><ul><li>59 - Interstitial nephritis </li></ul></ul><ul><li>Preeclampsia was associated with similar relative risk for development of ESRD due to a specific cause and for development of ESRD in general. </li></ul>
    45. 50. Summary of results <ul><li>Risk of development of ESRD among women with a history of previous preeclampsia was more than 3 times higher than risk among women without preeclampsia. </li></ul><ul><li>Results were significant even after adjustment for potential birth related confounders and exclusion of women who had a diagnosis of DM, HTN, kidney disease or rheumatic disease before their pregnancy. </li></ul><ul><li>However absolute risk is very low, even is women who had multiple episodes of preeclampsia. </li></ul>
    46. 51. Summary of results <ul><li>Association was stronger if the preeclamptic pregnancy resulted in a LBW or preterm infant. </li></ul><ul><ul><li>This suggests that severity of pre-eclampsia may be a marker for future ESRD risk. </li></ul></ul><ul><li>LBW or pre-term infant was a risk marker for ESRD, even in women who did not have preeclampsia. </li></ul><ul><ul><li>This suggests that placental dysfunction, even in the absence of preeclampsia, maybe a marker for future ESRD risk. </li></ul></ul>
    47. 52. Summary of results <ul><li>The risk of ESRD was greater in women with more than one preeclamptic pregnancy than in those with only one such pregnancy (“dose-response” effect). </li></ul><ul><li>Among women who had preeclampsia in only one of their pregnancies, the risk of ESRD was greater if preeclampsia occurred during the last pregnancy. (maternal age?, more severe dz?) </li></ul>
    48. 53. Strengths of the study <ul><li>Use of linked data from large national registries spanning over four decades. </li></ul>
    49. 54. Weaknesses of the study <ul><li>Accuracy of coding of preeclampsia in the Registry was not validated (However random misclassification would bias the results towards the null). </li></ul><ul><li>Accuracy of coding for diabetes was validated to be 98%, but for rheumatic disease it was only 88% and no validation studies were available to confirm accuracy of coding of HTN and kidney disease variables or BP and urinary dipstick measurement. (However, similar results after exclusion of women with these diagnoses). </li></ul><ul><li>Outcomes before 1980 were not registered and it is not clear how the patients who died before 1980 were dealt with. Depending on the incidence of ESRD and rates of mortality in the pre-eclampsia and non-preeclampsia groups, this could bias the results either way. </li></ul><ul><li>Information not available on BMI/Obesity - a recognized risk factor for both preeclampsia and ESRD (but, wouldn’t account for the entire magnitude of association). </li></ul><ul><li>Information on missing data unavailable. </li></ul>
    50. 55. Plausible explanations for the observed association <ul><li>Presence of underlying risk factors which predispose to both preeclampsia and ESRD. </li></ul><ul><ul><li>Obesity, HTN, insulin resistance and endothelial dysfunction have been linked to both diseases 1,2 . </li></ul></ul><ul><ul><li>Other observational studies done in early or mid pregnancy have shown that women in whom preeclampsia subsequently developed had higher BP (even within normal range), higher insulin levels and higher cholesterol levels than women who remained normotensive ,suggesting that factors pre-disposing to kidney disease antedated the preeclampsia 3 . </li></ul></ul><ul><li>References: </li></ul><ul><ul><li>Sibai et al. Risk factors for preeclampsia in healthy nulliparous women: a prospective multicenter study. AM J Obstet Gynecol 1995;172:642-8. </li></ul></ul><ul><ul><li>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. </li></ul></ul><ul><ul><li>Seely at al. Insulin resistance and it’s potential role in pregnancy induced hypertension. J Clin Endocrinol Metab 2003;88:2393-8. </li></ul></ul>
    51. 56. Plausible explanations <ul><li>Preeclampsia may exacerbate subclinical kidney disease leading to ESRD later in life. </li></ul><ul><ul><li>A study involving postpartum renal biopsies of women who had severe preeclampsia found previously unrecognized renal disease in more than 1 in 10 women, most frequently in those women with early onset of preeclampsia (before 30 weeks of gestation) 1 . </li></ul></ul><ul><ul><li>Reference: </li></ul></ul><ul><ul><li>Murakami et al. Renal disease in women with severe preeclampsia or gestational proteinuria. Obstet Gynecol 2000;96:945-9. </li></ul></ul>
    52. 57. Plausible explanations <ul><li>Preeclampsia may lead to ESRD later in life in some women. </li></ul><ul><ul><li>Other observational studies have found that 20-40% of women with pre-eclampsia have microabuminuria 3-5 yrs after pregnancy, as compared with only 2% of women without preeclampsia 1,2 . </li></ul></ul><ul><ul><li>References: </li></ul></ul><ul><ul><li>Bar et al. Microalbuminuria after pregnancy complicated by pre-eclampsia. Neprol Dial Transplant 1999;14:1129-32. </li></ul></ul><ul><ul><li>Nisell et al. Blood pressure and renal function seven years after pregnancy compicated by hypertension. Br J Obstet Gynaecol 1995;102:876-81. </li></ul></ul>
    53. 58. Conclusions <ul><li>Pre-eclampsia appears to be a clinical marker for an increased risk of HTN, endothelial dysfunction, CVD and possibly ESRD later in life (although the absolute risk is very low). </li></ul><ul><li>Further research is needed to better understand the underlying mechanisms and to guide clinical follow-up of women with history of pre-eclampsia. </li></ul>

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