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Kerstin Amann Nephropathology, Dept.of Pathology

Nephron number and essential hypertension – factors responsible for nephron load at the time of birth. Kerstin Amann Nephropathology, Dept.of Pathology Friedrich Alexander Universität Erlangen-Nürnberg Krankenhausstrasse 12 D-91054 Erlangen, Germany. Kidney and hypertension.

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Kerstin Amann Nephropathology, Dept.of Pathology

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  1. Nephron number and essential hypertension – factors responsible for nephron load at the time of birth Kerstin AmannNephropathology, Dept.of Pathology Friedrich Alexander Universität Erlangen-NürnbergKrankenhausstrasse 12 D-91054 Erlangen, Germany

  2. Kidney and hypertension „When the pulse is abundant but tense and hard and full like a cord, there are dropsical swellings……the kidney pass on the disease to the heart…“ (Yellow Emperor`s Classic of Internal Medicine, 2500 b.c.)

  3. Kidney and hypertension Sir Richard Bright(Guy`s Hospital Rep 1836;1:380):„...renal dysfunction is the primary cause of hypertension“

  4. Concept of Guyton Any increase in blood pressure should lead to a pressure natriuresis normalising blood pressure over the long term. (Guyton AC: Physiological regulation of arterial blood pressure. Am J Cardiol 1961) „As a conclusion, we have to assume that an elevation of arterial pressure can only be maintained if renal function as indicated by pressure natriu-resis is impaired.“ (Hall J, 2003)

  5. Kidney and hypertension • Renal transplantation studies in rat strains suggest that hypertension “goes with the kidney”.1-3 • Patients who received kidneys from a hypertensive donor tended to have higher blood pressures compared to patients with transplants from normotensive donors.4 • Individuals who endstage renal failure as a result of hyper-tension despite no primary renal disease became normo-tensive when they received well functioning allografts from a normotensive donor.5 1Bianchi et al: Clin Scien Mol Med 1974;2Dahl et al:Circ Res 1974; 3Rettig et al: Am J Phys 1990; 4Strandgaard et al: Brit Med J 1986; 5Curtis et al: N Engl J Med 1983

  6. Kidney and hypertension • Glomeruli and blood pressure. Less of one, more the other ?(Brenner et al., Am J Hypertens 1988; 1: 335-347) „...,we postulate that a renal abnormality that contributes to essential hypertension in the general population is a reduced number of nephrons.“

  7. The “Brenner-hypothesis” „nephron underdosing“ • Surgical Renal Ablation • Intrinsic Renal Disease • Solitary Kidney • Severe degrees of renal dysgenesis glomerular sclerosis reduction in filtration surface area/hyperfiltration glomerular / systemic hypertension NaRAAS  (Amann et al. Ped Nephrol 2004)

  8. Glomerular hyperfiltration and injury „The presence of relatively few glomeruli leads to increased filtration by each glomerulus. Over time this hyperfiltration may cause injury.“ (Ingelfinger J, NEJM 2003)

  9. Effect of neonatal nephrectomy in animal models • Woods et al. (Am J Physiol 1999):Neonatal nephrectomy causes hypertension in adult rats. • Woods et al. (Hypertension 2001):Hypertension after neonatal uninephrectomy in rats precedes glomerular damage. • Moritz et al. (Hypertension 2002):  Fetal uninephrectomy (in sheep) leads to postnatal hypertension and compromised renal function.

  10. Fetal uninephrectomy in sheep leads to postnatal hypertension and compromised renal function (Moritz et al. Hypertension 2002)

  11. Kidney and primary hypertension • convincing animal data and pathophysiological concepts, but lack of direct evidence in humans !

  12. Patients Case-control autopsy study (n=20) The pairs of the control group were matched in gender, age, height and weight. Selection criteria: 1) death before the age of 602) medical history of hypertension and / or concentric left ventricular hypertrophy3) characteristic arteriolar lesions of the kidney Exclusion criteria:1) any indications for secondary hypertension2) diabetes, alcohol or drug abuse3) history or evidence of renal disease by histological examination of the kidney

  13. Ancillary measurements Kidney were carefully analysed (HE, PAS, silver stains): • Semiquantitative score (0-3) of arte- riolar lesions and thickening of Bow- mans capsule • search for glomerular residues • percentage of obliterated glomeruli (per 100 glomeruli) • index (%) of periglomerular inflam- mation

  14. Patient characteristics

  15. Microscopical pictures of the kidney rim of an hypertensive individual (A) and a matched control (B) A B

  16. Number of glomeruli hypertensivepatients matched controls (Keller et al., NEJM 2003)

  17. Glomerular enlargement in hypertension

  18. Mean glomerular volume [x 10-3 mm3] hypertensivepatients matched controls (Keller et al., NEJM 2003)

  19. 11 1,200,000 P<0.0001 for Nglom Nglom 1,100,000 10 P=0.0002 for Vtuft Vtuft 1,000,000 9 Nglom Vtuft, um3x106 900,000 8 800,000 7 700,000 6 600,000 5 0 0 Hypertension No Hypertension 7.0 (6.0-7.9) 6.8 (6.0-7.5) Glomerular number, mean tuft volume and total glomerular tuft volume for individuals without (n=30) and with hypertension (n=50), USA series Vtufttot cm3 (Hughson et al,ASN 2004)

  20. < 10. percentile > 90. percentile Causes of reduced nephron number ? Genetic and/or environmental factors (epigenetic factors) Barker hypothesis (1992)(fetal programming of adult diseases) Changes in intrauterine milieu lead to growth retardation (IUGR), low birth weight and subsequent hypertension. rats: correlation of low birth weight and reduced nephron number17,18.humans: association between low birth weight and low kidney volume and recently between low birth weight and reduced nephron number19.

  21. r=0.423, p=0.0012, n=56regression coefficient predicts a gain of 257,426 glomeruli per kg increase in birth weight (Hughson et al. KI 2003)

  22. 1,200,000 11 P=0.01 for Nglom P=0.002 for Vtuft Nglom 1,100,000 10 Vtuft 1,000,000 9 900,000 8 Nglom Vtuft, um3x106 800,000 7 700,000 6 600,000 5 0 0 3.18-3.38 3.41-4.94 1.81-3.12 Tertiles of birthweight (kg) 6.6 (5.9-7.4) 6.7 (5.9-7.5) 6.8 (6.1-7.7) Glomerular number, mean tuft volume and total glomerular tuft volume by birthweight tertiles, US autopsy series, n=87 Vtufttot cm3 (Hughson, Kidney Int 2006)

  23. (Barker et al., 2006) (Hershkovitz et al. 2007) Low birth weigth and hypertension

  24. Potential mechanism of intrauterine programming of low nephron number and hypertension (Zandi-Nejat et al., Hypertension 2006)

  25. Low protein (LP) diet of the mothers during pregnancy (8% vs 20%) (Plank et al, Kidney Int 2006) Intrauterine growth retardation (IUGR) by low protein diet of the mother  25% lower number of nephrons, mild hypertension and renal alterations

  26. Maternal protein restriction suppresses the newborn RAS and programs adult hypertension(Woods et al., Ped Res 2001)

  27. Maternal protein restriction suppresses the newborn RAS and programs adult hypertension NP LP • Pax-2  apoptosis (Woods et al., Ped Res 2001)

  28. 2,0 r=0,43 p=0,001 1,5 -HSD2/GAPDH 1,0 (relative units) b 11 0,5 0,0 2000 2500 3000 3500 4000 4500 Birth weight (g) Placental 11-HSD2 (Hydroxysteroid Dehydrogenase)expression in relation to birth weight  converts cortisol to the biologically less active cortison (Schoof et al., J Clin. Endocrinol. Metab. 2001)

  29. p<0.05 Reduced expression of 11ßHSD in IUGR rats with lower nephron number due to LP diet (Östreicher et al. NDT 2010)

  30. Factors involved in kidney development pronephros mesonephros metanephros

  31. GDNFand kidney development induces sprouting of ureteric bud from Wolffian duct GDNF regulation and expres-sion by: Pax2, Six2, Eya1 (Davies et al. Exp Nephrol 2002)

  32. * Nephron number per kindey 15000 10000 5000 0 wildtyp GDNF +/- Mean glomerular volumen (103 µm3) * 2000 1000 0 wildtyp GDNF +/- GDNF +/- mouse • Genetic background: Hybrid 129/Sv and C57BL/6 • 25 % lower kidney weight (or unilateral kidney aplasia) • 30% less nephrons • mild hypertension (+18 mmHg) at 14 months of age (Cullen-McEwen et al., Kidney Int 2001, Hypertension 2003, Benz et al. GfN 2007)  suitable animal model to study the effect of low nephron number !

  33. F E Glomerular hypertrophy in GDNF+/- with lower nephron number GDNF+/- wildtype → significant reduction in podocyte density

  34. Early changes of glomerular ultrastructure in GDNF+/- with lower nephron number wildtype GDNF+/-

  35. Reduced filtra- tion area glomerulo- sclerosis increase / hyperfiltration of remaining glomeruli glomerular / systemic hypertension Na-channels ?Na-retention ? RAAS  ? Impaired renal development Maternal of fetalcauses Environmental factors Lower kidney mass or nephron number Loss of renal mass during a sensitive periode, mismatch

  36. Practical conclusion Bagby S: Developmental Origins of Renal Disease: Should Nephron Protection Begin at Birth? (Clin J Am Soc Nephrol 2009) → early identification of individual patients at risk by birth weight and gestational age

  37. Thank you ! Glomunculus

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