The role of fetal programming in pathogenesis of arterial hypertension and kidney disease in the adult life

Size: px

Start display at page:

Download "The role of fetal programming in pathogenesis of arterial hypertension and kidney disease in the adult life"

Carol Kelley
5 years ago
Views:

22. NATIONAL CONGRESS OF RENAL DISEASES, DIALYSIS & TRANSPLANTATION NURSING

TRANSPLANTATION Antalya, 14-18 November 2012 The role of fetal programming

1 22. NATIONAL CONGRESS OF RENAL DISEASES, DIALYSIS & TRANSPLANTATION NURSING 29. NATIONAL CONGRESS OF NEPHROLOGY, HYPERTENSION DIALYSIS & TRANSPLANTATION Antalya, November 2012 The role of fetal programming in pathogenesis of arterial hypertension and kidney disease in the adult life Prof. Andrzej Wiecek Department of Nephrology, Endocrinology and Metabolic Diseases Medical University of Silesia, Katowice, Poland

2 Animal experiments: blood pressure goes with the kidney Kidney genetically programmed for hypertension, transplanted into a normotensive recipient animal with no immune rejection persistent hypertension Rettig R., Am J Physiol, 1990, 258, F606

3 Primary hypertension role of the kidney SHR Wild type RR RR N RR RR Rettig R. et al. Am J Physiol. 1990;258: Patschan O. et al. Am J Physiol. 1997; 273:

4 Blood pressure increase in kidney allograft recipients from hypertensive donor (SHR) Rettig R. et al., Am. J. Physiol., 1989, 257, F197-F203

5 B.J.P. Barker, Lancet, 1986, 1, 1077 The origin of Barker s hypothesis - Fetal programming hypothesis

6 Barker hypothesis x Br. Med. J., 1989, 289,

7 x Brit. Med. J.; 1993, 306: 24

8 x Brit. Med. J.; 1993, 306: 24

9 Low birth weight as a marker of impaired fetal development WHO definition of low birth weight (LBW) is defined as the weight of live born infants less than 2,500 g Birth weight below the 10th percentile for that gestational age a marker for intrauterine growth restriction (IUGR) Low birth weight in prematurity children birth weight appropriate for gestational age, but small in comparison to children born on time

10 Prenatal programming Abnormalities of kidney structure ( nephron underdosing ): may predispose to hypertension and increase the susceptibility to renal damage in the adult life Brenner, Am J Hypert ; 1988, 1, 335

11 Correlation between birth weight, number (A) and volume (B) of glomeruli A r = 0.870, P < r = 0.840, P < B Manalich R et al. Kidney Int., 2000: 58 ;

12 Correlation between birth weight and nephron number Hughson, Kidney Int. 2003, 2113

13 Hypertensive individuals (n=10) Normotensive individuals (n=10) Number of glomeruli 890,869 1,666,805 p < ± 158,110 ± 411,690 Volume of glomeruli p < ± 0.85 ± 0.71 no evidence of obsolescent glomeruli as evidence of hypertension induced loss of glomeruli Keller, N Engl J Med.; 2003, 348, 101

14 Oligomeganephrony number volume Keller, N Engl J Med; 2003, 348, 101

15 Hypertension Normotension x Keller, N Engl. J. Med.; 2003, 348, 101

16 Low birth weight higher adolescent blood pressure (2-3mmHg) Rotterdam study: Uiterwaal, Hypertension; 1997, 30:267 Higher catch up growth adult fatness obesity related blood pressure Horta, J.Epidemiol. Community Health; 2003, 57: 226 Huxley, J.Hypertens.; 2000, 18:815

17 Low birth weight and hypertension Helsinki study Koleganova N. Piecha G., Ritz E. Blood Purif., 2009, 27, 48-52

18 Outcome after unilateral renal agenesis (pre/perinatal) 157 patients with unilateral agenesis and normal contralateral kidney Mean age 37 years # proteinuria 150 mg/day 19% # high blood pressure 47% # reduced renal function 13% # 6 deaths from renal failure Argueso, Ped. Nephrology; 1992, 6:412

19 No gross excess hypertension in live kidney donors 402 alive kidney donors proteinuria 12 % - hypertension 38% not exceeding rate in matched background population Fehrman-Ekholm, Transplantation; 2001, 72:444

20 Less glomeruli, but glomeruli bigger calculated index of filtration surface was normal Hypothesis High blood pressure is not a result of low glomerular number per se (less, but bigger glomeruli normal filtration surface) but is a result of developmental changes in postglomerular segments ( higher sodium reabsorption)

21 Main mechanisms contributing to hypertension from prenatal programming Upregulation of sodium channels Upregulation of RAS (AT1-R) Cortisol (11βHSD2 ) mineralocortocoid receptor Sympathetic overactivity

22 Low birth weight salt sensitivity of blood pressure in healthy adults de Boer, Hypertension; 2008, 51: 928

23 Mean Arterial Pressure (mmhg) Decreased nephron number shifts pressure natriuresis relationship to the right 6 Normal nephron loss 5 Urinary Sodium Output (x normal) 4 3 High Intake Salt-sensitive 2 1 Normal Intake 0

24 Causes of reduced glomerular numbers (in animal experiments) maternal pathology impaired nephrogenesis of offspring Low protein intake Uterine underperfusion Maternal hyperglycemia Maternal hyperinsulinemia High and low maternal salt intake Corticosteroids Woods, Pediatr. Res.; 2001, 49:460 Wlodek, Kidney Int.; 2008, 74:187 Amri. Diabetes ; 2001, 50:1069 Bursztyn, Hypertension ; 2006, 48:717 Balbi, Pediatr. Nephrol ; 2004, 19:1212 Koleganova N et al. Am J Physiol Renal Physiol. 2011, 301, F344-F354 Woods, Am.J.Physiol.; 2005, 289: R955 Alcohol (ethanol) consumption Gray, J. Am. Soc. Nephrol.; 2010, 21: 1891 Smoking and CyA Zarzecki M at al. Słabiak-Błaż et al. (Submitted)

25 Maternal protein restriction *p< 0,05 compared with control Woods L., Ingelfinger J., Nyengaard et al. Pediatr Res 2001; 49: NP- normal protein diet LP- low protein diet

26 Maternal protein restriction reduces nephron number in multiple species Bagby S et al. J. Nutr. 2007, 137:

27 Maternal hyperglycemia Amri K. et al. Diabetes. 1999:48;

(Dia-Offsprings) offspring of diabetic mothers with insulin treatment (Ins- Treated

28 Maternal diabetes programs hypertension and kidney injury in offspring Murine study, 3 groups: offspring from non-diabetic mothers (Con-offsprings) offspring from diabetic mothers (Dia-Offsprings) offspring of diabetic mothers with insulin treatment (Ins- Treated Offspring) SYSTOLIC BLOOD PRESURE **p 0.01, ***p Yun-Wen Chen et al. Pediatr Nephrol 2010, 25:

PAI 1 and TGF-β expression in kidney *p 0.05, **p 0.

001 ECM(extracellular matrix) protein expression in

29 Maternal diabetes programs hypertension and kidney injury in offspring Urinary albumin/creatinine ratio PAI 1 and TGF-β expression in kidney *p 0.05, **p 0.01, ***p ECM(extracellular matrix) protein expression in glomeruli by PAS staining of kidney sections Yun-Wen Chen et al. Pediatr Nephrol, 2010, 25:

Maternal diabetes programs hypertension and kidney injury in offspring Real-time quantitative polymerase chain reaction (RT-qPCR) of intrarenal renin angiotensin system (RAS) components.

30 Maternal diabetes programs hypertension and kidney injury in offspring Real-time quantitative polymerase chain reaction (RT-qPCR) of intrarenal renin angiotensin system (RAS) components. The relative densities of angiotensinogen (Agt), angiotensin II (subtype 1) receptor (AT1R), angiotensinconverting enzyme (ACE), and angiotensinconverting enzyme-2 (ACE2) in the renal cortex of 20-weekold male offspring *p 0.05, **p 0.01, ***p 0.00 Yun-Wen Chen et al. Pediatr Nephrol (2010) 25:

31 Both high and low maternal salt intake in pregnancy alters kidney development in the offspring

32 Both high and low maternal salt intake in pregnancy alters kidney development in the offspring Mean arterial blood pressure (MAP) measured by intraaortal telemetry in offspring. x *p<0.05 HS or LS vs IS HS - high sodium LS - low sodium IS - intermediate s odium

33 High salt diet in pregnant rats high albuminuria in offspring 0,15% 1,3% 8% Koleganova N et al. Am J Physiol Renal Physiol. 2011, 301, F344-F354

34 Maternal plasma vitamin A level vitamin A and all-trans retinoic acid are potent stimulators of nephrogenesis influence on ureteric bud branching capacity ( i.e.by glial cell-line-derived neurotrophic factor GDNF) Merlet-Benichou c. et al. J. Dev. Biol. ;1999: 43;

35 Smoking during pregnancy

36 Smoking during pregnancy In UK 17% pregnant women are smoking 45% pregnant women <20 years are smoking In USA 20% pregnant women <25 years are smoking 9% pregnant women >35 years are smoking In Poland 33% pregnant women are smoking 12% are smoking 3 months before delivery

37 Exposure to cigarette smoke condensate during pregnancy influence on kidney morphology in offspring Mean glomerular volume Podocyte number per glomerulus Zarzecki M.. Wiecek A., Kidney Blood Pressure Res., 2012, 36,

600 300 Urinary sodium excretion 531±242 846±384 p<0.05 [mmhg] p<0.

38 Exposure to cigarette smoke condensate during pregnancy influence on blood pressure and natiuresis in offspring Systolic blood pressure at 12 weeks of age 122±7 116±8 [µmol/24 hours] Urinary sodium excretion 531± ±384 p<0.05 [mmhg] p< Urinary sodium/creatinine ratio ± ±4.2 Cigarette smoke Control condensate n=51 n=53 [μmol/μmol] p<0.05 0

39 x J. Hypertens., 2012, 30,

40 Prenatal exposure to ethanol results in a reduction in nephron number MALE FEMALE ***p<0,001 **p<0,01 Gray S. et al. J Am Soc Nephrol 2010; 21:

41 Prenatal exposure to ethanol results in a larger mean glomerular volume MALE FEMALE *p<0,005 **p<0,01 Gray S. et al. J Am Soc Nephrol 2010; 21:

42 Prenatal exposure to ethanol increases mean arterial pressure MALE FEMALE *p<0,005 **p<0,01 Gray S. et al. J Am Soc Nephrol 2010; 21:

43 Prenatal exposure to ethanol results in increased proteinuria Gray S. et al. J Am Soc Nephrol 2010; 21:

Influence of ethanol on culture of embryonic metanephroi Number of ureteric branch points Number of ureteric tips Number of glomeruli Immunofluorescence images showing

44 Influence of ethanol on culture of embryonic metanephroi Number of ureteric branch points Number of ureteric tips Number of glomeruli Immunofluorescence images showing the ureteric trees in whole rat metanephroi after 48 hours of culture in 0% ethanol (A and B) and 0,2% ethanol (C and D) Gray S. et al. J Am Soc Nephrol 2010; 21:

45 List of drugs influencing renal development Schreuder M. et al. Clin J Am Soc Nephrol 2011; 6:

46 Effect of cyclosporine A administration in pregnant rats on number and volume of glomeruli in their offspring Number of glomeruli Volume of glomeruli p< ,5 p<0.001 [Number] [x10 6 μm 3 ] 2 1,5 1 0,5 0 0 Cyclosporine A Solvent Słabiak-Błaż N., Adamczak M., Koleganova N, Nyengaard JR, Ritz E., Więcek A. ASN Philadelphia 2011

offspring at 7 th and 11 th weeks of age [mmhg] 120 80 40 [mmhg] 80 40 0 7 th week 11 th week 0 7 th week 11

47 Effect of cyclosporine A administration in pregnant rats on blood pressure in their offspring SYSTOLIC BLOOD PRESSURE measured in offspring at 7 th and 11 th weeks of age DIASTOLIC BLOOD PRESSURE measured in offspring at 7 th and 11 th weeks of age [mmhg] [mmhg] th week 11 th week 0 7 th week 11 th week Solvent Cyclosporine A Słabiak-Błaż N., Adamczak M., Ritz E., Więcek A. et al. ERA-EDTA, Praha, 2011

48 Fetal exposure to steroides Normal situation Severe maternal stress, external steroids i.e dexamethason Seckl J. et al. J. Nat Clin Pract Endocrinol Metab. 2007; 3:

49 Fetal exposure to steroides Seckl J. et al. KI 2000; 57:

50 Fetal exposure to steroides x Moritz K. et al. Cell Tissue Res 2005; 322: 81-88

IUGR is associated with persistent aortic wall thickening and glomerular proteinuria during infancy 44 mothers with single-fetus pregnancies at 32 weeks gestation:

51 IUGR is associated with persistent aortic wall thickening and glomerular proteinuria during infancy 44 mothers with single-fetus pregnancies at 32 weeks gestation: 23 growth restricted (IUGR) and 21 of appropriate gestational age (AGA) as controls Urine microoalbuminuria in infants Zandaro V. et al. Kidney Int.,2011,80,

53 Piecha G. et al., Nephrol. Dial. Transplant. 2012, 27,

54 Urine microalbumin in intrauterine growth restricted (IUGR) and appropriate for gestational age (AGA) infants Median (interquartile range) 11.1 vs 4.4 mg/l P<0.001 Zanardo V. et al. Kidney Int., 2011, 80:

55 Association between low birth weight (<2500g) and CKD in adult life: meta-analysis White S. Am J Kidney Dis 2009; 54:

56 Albuminuria (microalbuminuria, age 50) Effect of the Dutch Famine (During World War II for a 6 month period the rations fell to below 1000 kcal in one part of the Netherlands) on albuminuria 50 years later Babies who were exposed to this starvation during the midterm period had a 2-3 times increased risk for albuminuria 50 years later Born before (Ref.) Late Mid Early This study included 700 people and they also adjusted for cardiovascular risk factors in adult age Painter R. J Am Soc Nephrol 2005; 16:

57 ESDR (risk for RRT during first 38 years of life) Vikse BE. J Am Soc Nephrol 2008; 19:

Low egfr (< sex specific 10th percentile age 20-30) 7500

adjustment for both maternal and for adult risk factors

58 Low egfr (< sex specific 10th percentile age 20-30) 7500 people from the population based HUNT 2 cohort Birth weight <2500g was associated with a 2.4 times increased risk for low egfr in men, also after adjustment for both maternal and for adult risk factors The risk in women was not increased at all Hallan S. Am J Kidney Dis 2007; 51: 10-20

59 Prenatal programming Epigenetics : nutritional deprivation, placental malfunction, hyperglycemia, smoking in pregnancy Hypertension Kidney disease, Metabolic syndrome in the adult life Barker, Nat. Clin. Pract.Nephrol.; 2006, 2: 700

60 Mechanisms of Programming Nutritional Influence Altered Cell Number or intracellular organization Reorganisation of organ structure Abnormal early cell-cell interactions? Metabolic Differentiation DNA Control? (altered cell specific gene regulation) DNA Environment? (altered DNA binding proteins) Altered DNA methylation?

61 Mechanisms of epigenetic changes during fetal development

62 Changes in gene expression by epigenetic modifications Gicquel et al. Best Pract Res Clin Endocrinol Metab. 2008; 22:1-16

63 Changes in gene expression by epigenetic modificationsdifferent fenotype Gicquel et al. Best Pract Res Clin Endocrinol Metab. 2008; 22:1-16

64 Cardiovascular and renal diseases: The multi-hits hypothesis Simeoni U. et al. Pediatr Nephrol, 2011, 26:

65 Cardiovascular and renal diseases: The multi-hits hypothesis Simeoni U. et al. Pediatr Nephrol, 2011, 26:

66 Cardiovascular and renal diseases: The multi-hits hypothesis Simeoni U. et al. Pediatr Nephrol, 2011, 26:

67 Cardiovascular and renal diseases: The multi-hits hypothesis Simeoni U. et al. Pediatr Nephrol, 2011, 26:

68 Factors that directly or indirectly affect fetal development and may thus favour programming of diseases that occur in later life x Koleganowa N. et al. Nephrol. Dial. Transplant., 2012, 27,

69 How can we identify patients with potentially impaired intrauterine development who are at risk for prenatally programmed diseases in later life? Koleganowa N. et al. Nephrol. Dial. Transplant., 2012, 27,

70 Thank you for your attention! Andrzej Wiecek Katowice

The kidney and hypertension. Eberhard Ritz Heidelberg (Germany)

The kidney and hypertension. Eberhard Ritz Heidelberg (Germany) The kidney and hypertension Eberhard Ritz Heidelberg (Germany) The epidemic of hypertension in the USA Hypertensives (% of population throughout the 20 th century) 1939: 10.0% 1975: 25.3% 1990: 28.9% 2000: