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 12D-91054 Erlangen, Germany

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.)

Kidney and hypertension

Sir Richard Bright (Guy`s Hospital Rep 1836;1:380):

„...renal dysfunction is the primary cause of hypertension“

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)

(Hall J, 2003)

„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.“

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

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.“

glomerular / systemic

hypertension

glomerular

sclerosis

reduction in filtration surface

area/hyperfiltration

The “Brenner-hypothesis”The “Brenner-hypothesis”

(1) Surgical Renal Ablation

(2) Intrinsic Renal Disease

(3) Solitary Kidney

(4) Severe degrees of renal dysgenesis

„nephron underdosing“

NaRAAS

(Amann et al. Ped Nephrol 2004)

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)

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.

Fetal uninephrectomy in sheep leads to postnatal hypertension and compromised renal function

(Moritz et al. Hypertension 2002)

Kidney and primary hypertension

convincing animal data and pathophysiological concepts,

but lack of direct evidence in humans !

PatientsPatients

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

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

Patient characteristics

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

A B

Number of glomeruli

702,379

1,429,200

0

250000

500000

750000

1000000

1250000

1500000

1750000

2000000

2250000

1 2hypertensivepatients

matched controls

(Keller et al., NEJM 2003)

Glomerular enlargement in hypertension

Mean glomerular volume

6.495

2.785

0

1

2

3

4

5

6

7

8

9

1 2matched controlshypertensivepatients

[x 10-3 mm3]

(Keller et al., NEJM 2003)

Glomerular number, mean tuft volume and total glomerular tuft volume for individuals without (n=30) and with hypertension

(n=50), USA series

Vtufttot cm3

Nglom

Vtuft

600,000

700,000

800,000

900,000

1,000,000

1,100,000

1,200,000

No Hypertension Hypertension

Ng

lom

5

6

7

8

9

10

11V

tuft, u

m3x10

6

0 0

7.0 (6.0-7.9) 6.8 (6.0-7.5)

P<0.0001 for Nglom

P=0.0002 for Vtuft

(Hughson et al, ASN 2004)

Causes of reduced nephron number ?

Genetic and/or environmental factors (epigenetic factors)

Barker hypothesis (1992) (fetal programming of adult diseases)

< 10. percentile > 90. percentile

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.

Changes in intrauterine milieu lead to growth retardation (IUGR), low birth weight and subsequent hypertension.

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)

Glomerular number, mean tuft volume and total glomerular tuft volume by birthweight tertiles,

US autopsy series, n=87

Vtufttot cm3

Tertiles of birthweight (kg)

600,000

700,000

800,000

900,000

1,000,000

1,100,000

1,200,000

1.81-3.12 3.18-3.38 3.41-4.94

Ngl

om

5

6

7

8

9

10

11

Vtuft, um

3x106

0 0

Nglom

Vtuft

6.7 (5.9-7.5) 6.8 (6.1-7.7) 6.6 (5.9-7.4)

P=0.002 for Vtuft

P=0.01 for Nglom

(Hughson, Kidney Int 2006)

Low birth weigth and hypertension

(Barker et al., 2006)(Hershkovitz et al. 2007)

Potential mechanism of intrauterine programming of low nephron number and hypertension

(Zandi-Nejat et al., Hypertension 2006)

Intrauterine growth retardation (IUGR) by low protein diet of the mother

(Plank et al, Kidney Int 2006)

Low protein (LP) diet of the mothers during pregnancy (8% vs 20%)

25% lower number of nephrons, mild hypertension and renal alterations

Maternal protein restriction suppresses the newborn RAS and programs adult hypertension

(Woods et al., Ped Res 2001)

Maternal protein restriction suppresses the newborn RAS and programs adult hypertension

NP

LP

Pax-2 apoptosis

(Woods et al., Ped Res 2001)

Placental 11-HSD2 (Hydroxysteroid Dehydrogenase) expression in relation to birth weight

(Schoof et al., J Clin. Endocrinol. Metab. 2001)

2000 2500 3000 3500 4000 45000,0

0,5

1,0

1,5

2,0

Birth weight (g)

11

-HS

D2/

GA

PD

H(r

elat

ive

un

its)

r=0,43 p=0,001

converts cortisol to the biologically less active cortison

Reduced expression of 11ßHSD in IUGR rats with lower nephron number due to LP diet

(Östreicher et al. NDT 2010)

p<0.05

Factors involved in kidney development

pronephros mesonephros metanephros

(Davies et al. Exp Nephrol 2002)

GDNF and kidney development

induces sprouting of ureteric bud from Wolffian duct

GDNF regulation and expres-sion by: Pax2, Six2, Eya1

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)

Nephron number per kindey

wildtyp GDNF +/-0

5000

10000

15000 *

Mean glomerular volumen (103 µm3)

0

1000

2000

wildtyp GDNF +/-

*

suitable animal model to study the effect of low nephron number !

Glomerular hypertrophy in GDNF+/- with lower nephron number

E F

wildtype GDNF+/-

→ significant reduction in podocyte density

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

wildtype GDNF+/-

Maternal of fetalcauses Environmental factors

Lower kidney mass or

nephron number

Na-channels ?Na-retention ?RAAS ?

Reduced filtra-

tion area

glomerular / systemic

hypertension

glomerulo-

sclerosis

increase / hyperfiltration of

remaining glomeruli

Impaired renal development

Loss of renal mass during a

sensitive periode, mismatch

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

Glomunculus

Thank you !