Renal Changes

during Pregnancy

Waleed Elrefaey MD
Lecturer of Internal Medicine
Nephrology Division
Faculty of Medicine, Tanta University
 AGENDA
• Structural Changes
• Systemic Changes:
 Osmoregulation
 Volume Regulation
 Endocrinal Changes
 Systemic Hemodynamics
 Electrolytes
• Renal Hemodynamics
• Renal Tubular Function
• Impact on Fetal Programming
Renal Changes during Pregnancy

• Substantial structural and functional changes take place as

a maternal adaptation to normal pregnancy.

• A state of new temporary norm, due to alterations in:

• Distinguish normal from compromised pregnancies.

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Structural Changes

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Structural Changes

• Increase in renal bipolar diameter.

3-6 months
1-1.5 cm
By 26th week

Non pregnant 1st Trimester 2nd Trimester 3rd Trimester Postpartum

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Structural Changes

Kidney volume enlarges Physiologic hydronephrosis

by about 30% because
of increments in both
vascular and interstitial
Mechanical Smooth muscle–
fluid compartments.
compression by the relaxing effect of
enlarging uterus progesterone

Urinary stasis predisposes pregnant

women with asymptomatic bacteriuria to
develop acute pyelonephritis.
Ogueh O, Clough A, Hancock M, Johnson MR. A longitudinal study of the control of renal and uterine hemodynamic changes of
pregnancy. Hypertens Pregnancy. 2011;30:243-259.
Rasmussen PE, Nielson FR. Hydronephrosis in pregnancy: a literature survey. Eur J Obstet Gynecol Reprod Biol. 1988; 27(3):249–259.

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Structural Changes

Intravenous urogram at 36 weeks’ gestation

The right ureter crosses the iliac and ovarian vessels at a more acute
angle than left ureter before entering the pelvis

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Structural Changes

Threshold for development: 20 weeks

Maximal incidence: 28 weeks
Overall incidence: 63%

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Structural Changes

• Physiologic Proteinuria:
• Urine protein excretion increases during the course of normal
pregnancy, up to 250 mg/day.

• Gestational proteinuria has been attributed to:

1. Hyperfiltration.
2. Increase in glomerular membrane pore size and permeability in
the absence of a change in hydrostatic force.
3. As well as alterations in proximal tubular function.

• The threshold for pathological proteinuria in pregnancy has been

set at a protein excretion more than 300 mg/day or
(UPCR > 0.3 g/g).

Milne, J. E. C., Lindheimer, M. D. & Davison, J. M. Glomerular heteroporous membrane modeling in third trimester and postpartum before
and during amino acid infusion. Am. J. Physiol. Renal Physiol. 282, F170–F175 (2002).

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Structural Changes

an increase of 150 mg/g in singleton pregnancies and 220

mg/g in twin pregnancies at 34–38 weeks of gestation.
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Structural Changes

• In pre-eclampsia, studies have described the release of soluble

antiangiogenic factors from the ischemic placenta that are
injurious to the vascular endothelium, and disrupt the slit
diaphragm.

• The balance of angiogenic and antiangiogenic factors provides

further insights in protein excretion even in healthy pregnancy.

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Structural Changes

soluble fms-like tyrosine kinase 1

Placental growth factor VEGF

VEC

• The resultant maternal endothelial dysfunction is best

demonstrated at the level of the glomerulus in which GFR
depression and proteinuria are a direct result of glomerular
endotheliosis.
Maynard SE, et al: Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction,
hypertension, and proteinuria in preeclampsia. J Clin Invest 111: 649–658, 2003

Lafayette RA, Druzin M, Sibley R, Derby G, Malik T, Huie P, Polhemus C, Deen WM, Myers BD: Nature of glomerular
dysfunction in pre-eclampsia. Kidney Int 54: 1240–1249, 1998
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Structural Changes

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Structural Changes

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Systemic Changes

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Systemic Changes
Osmoregulation Volume Regulation

Systemic Hemodynamics

Endocrinal Changes Electrolytes

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Systemic Changes

 Osmoregulation
• Early in pregnancy, plasma osmolality decreases
to recognize the 10 mOsm/kg below the
reduced plasma nonpregnant norm because of
osmolality and a reduction in serum sodium
expanded plasma and associated anions.
volume as normal.

Plasma volume status

(a nonosmotic
The osmotic threshold for The threshold determinant of ADH
antidiuretic hormone for thirst release) is also reset
(ADH) release
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Systemic Changes

 Osmoregulation
• Human chorionic gonadotropin (which stimulates the release of
ovarian relaxin) may have a role in this reduction of the osmotic
threshold for ADH release.

The metabolic clearance rate of Plasma ADH

ADH has increased four times at concentrations are
week 10 and through midpregnancy usually kept normal in
because of the release of enzyme pregnancy because of
vasopressinase from the placenta. increased secretion.
Lindheimer MD, Davison JM. Osmoregulation, the secretion of arginine vasopressin and its metabolism during pregnancy. Eur J
Endocrinol. 1995;132:133-143.

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Systemic Changes

 Volume Regulation

• The increase in plasma volume (1.2-1.6 liters) takes place

progressively up to 32 to 34 weeks, after which there is little
further change.

• The increase in plasma renin, angiotensin and aldosterone

concentrations of normal pregnancy suggests an underfill signal

• due to peripheral vasodilatation, that leads to renal sodium and

water retention.

Schrier RW. Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis and
pregnancy. Part 2. N Engl J Med. 1988;319:1127-1134.

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Systemic Changes

 Volume Regulation

• The tubuloglomerular feedback system is suppressed by volume

expansion in the nonpregnant state.

• but in pregnancy, is reset to recognize the expanded volume and

increased GFR as normal.

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Systemic Changes

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Systemic Changes

 Endocrinal Changes:
Physiological changes strongly relate to the renal synthesis of or
renal response to several hormones.

Progesterone:
Early on, luteal phase progesterone plays a role in increasing the RPF
and GFR, and this role may continue during pregnancy.

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Systemic Changes

 Endocrinal Changes:
RAAS:
• Increased renin is produced by renal and extrarenal sources (the
ovaries and decidua).

• Angiotensinogen production by the liver increases under the

influence of estrogen.

• Aldosterone levels are higher during normal pregnancy.

Chapman AB, Zamudio S, Woodmansee W, et al. Systemic and renal hemodynamic changes in the luteal phase of the menstrual cycle
mimic early pregnancy. Am J Physiol. 1997; 273(5 Pt 2):F777–F782.

Sibai BM, Ramadan MK. Acute renal failure in pregnancies complicated by hemolysis, elevated liver enzymes, and low platelets. Am J
Obstet Gynecol. 1993; 168(6 Pt 1):1682–1687.

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Systemic Changes

 Endocrinal Changes:
RAAS:
• However, vasodilation takes place during pregnancy:
 Progesterone and vascular endothelial growth factor (VEGF)-
mediated prostacyclins increase refractoriness to angiotensin II.
 Angiotensin II type 1 (AT1) receptors are less responsive during
normal pregnancy as they exist in a monomeric state.

Chapman AB, Zamudio S, Woodmansee W, et al. Systemic and renal hemodynamic changes in the luteal phase of the menstrual cycle
mimic early pregnancy. Am J Physiol. 1997; 273(5 Pt 2):F777–F782.
Sibai BM, Ramadan MK. Acute renal failure in pregnancies complicated by hemolysis, elevated liver enzymes, and low platelets. Am J
Obstet Gynecol. 1993; 168(6 Pt 1):1682–1687.
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Systemic Changes

 Endocrinal Changes:
Relaxin:
• Relaxin, produced by the corpus luteum, decidua and placenta,
increases RPF, GFR and solute clearance by afferent and efferent
vasodilation.

• This is mediated through upregulation of nitric oxide-dependent

vasodilation.

Jeyabalan A, Novak J, Danielson LA, et al. Essential role for vascular gelatinase activity in relaxin-induced renal vasodilation,
hyperfiltration, and reduced myogenic reactivity of small arteries. Circ Res. 2003; 93:1249–1257.

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Systemic Changes

 Endocrinal Changes:

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Systemic Changes

 Endocrinal Changes:
Erythropoietin
• Gestational increases in plasma volume in pregnancy are
proportionally higher than the corresponding increase in red
blood cell mass,

• leading to haemodilution and a relative fall in haemoglobin

levels. (Normal Hb level= 10.5 – 11 mg/dl, hematocrit= 33%)

• Erythropoietin concentrations increase approximately 2 fold

during pregnancy.

McMullin, M. F., White, R., Lappin, T., Reeves, J. & MacKenzie, G. Haemoglobin during pregnancy: relationship to erythropoietin and
haematinic status. Eur. J. Haematol. 71, 44–50 (2003).
Turner, M., Barré, P. E., Benjamin, A., Goltzman, D. & Gascon-Barré, M. Does the maternal kidney contribute to the increased circulating
1,25-dihydroxyvitamin D concentrations during pregnancy? Miner. Electrolyte Metab. 14, 246–252 (1988).

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Systemic Changes

 Endocrinal Changes:
Vitamin D

• Serum calcitriol levels (1,25-dihydroxyvitamin D3) are

approximately 3 fold higher in the first trimester and 5-6 times
higher in the third trimester than those in nonpregnant women.

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Systemic Changes

 Systemic Hemodynamics
% Increase
Cardiac output significantly
50
increases by the 5th gestational week
40

30
Heart Stroke
Rate Volume
20

10

5th 8th 26th

1st Trimester 2nd Trimester 3rd Trimester

Ogueh O, Brookes C, Johnson MR. A longitudinal study of the cardiovascular adaptation to spontaneous and assisted conception
pregnancies. Hypertens Pregnancy. 2009;28:273-289.

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Systemic Changes

 Systemic Hemodynamics

• Pregnancy is a state of profound physiological vasodilatation with

mediators (including progesterone, nitric oxide and
prostaglandins) and reduction in systemic vascular resistance

• leading to a 5–10 mmHg reduction in blood pressure during

pregnancy.

Magness RR, Gant NF. Normal vascular adaptations in pregnancy: Potential clues for understanding pregnancy induced hypertension.
In: Walker JJ, Gant NF, eds. Hypertension in Pregnancy. London: Chapman & Hall Medical; 1997:5-26.

Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase (sFlt1) may contribute to endothelial
dysfunction, hypertension and proteinuria in preeclampsia. J Clin Invest. 2003;111:649-658.

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Systemic Changes

 Systemic Hemodynamics

• Organ blood flow increases in pregnancy, with the most dramatic

changes occurring in

 the kidney and skin circulation throughout gestation and

 in the uterus in the second part of the pregnancy.

Ogueh O, Clough A, Hancock M, Johnson MR. A longitudinal study of the control of renal and uterine hemodynamic changes of
pregnancy. Hypertens Pregnancy. 2011;30:243-259.

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Systemic Changes

 Electrolytes
Pregnancy is characterized by increments in total body electrolyte
stores, albeit with decrements in serum levels because of greater
retention of water.

Sodium:
Total body sodium
 Increases on an average by 3–4 mEq/d,
 producing a net balance of 900-1000 mEq by the end of
gestation.
 serum level decrease by 4 mEq/L.

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Systemic Changes

 Electrolytes

Sodium:
Retention of sodium is a complex interplay of natriuretic and
antinatriuretic factors,

Factors Influencing Sodium Excretion

During Pregnancy
Natriuretic Antinatriuretic
Increased GFR Aldosterone (+kaliuretic)
Atrial natriuretic peptide Angiotensin II
Progesterone (+Antikaliuretic) Estrogen
Nitric oxide Deoxycorticosterone
Prostaglandins Na+/K+ transporters

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Systemic Changes

 Electrolytes

Sodium:

• Progesterone attenuates sodium reabsorption by competitively

inhibiting aldosterone at the tubular mineralocorticoid receptor.

• Other factors that may promote natriuresis include decrease in

serum albumin concentration and increase in prostaglandins and
melanocyte stimulating hormone.

Davison JM, Lindheimer MD: Volume homeostasis and osmoregulation in human pregnancy. Baillieres Clin Endocrinol Metab
3: 451–472, 1989

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Systemic Changes

 Electrolytes

Potassium:
• Total body potassium store increases by up to 320 mEq by the
end of gestation,

• but its serum level decreases by 0.25 mEq/L due to hemodilution.

• The decrease in potassium excretion occurs despite the high

aldosterone values of normal pregnancy, caused by the potent
antimineralocorticoid action of progesterone.

Lindheimer MD, Richardson DA, Ehrlich EN, Katz AI. Potassium homeostasis in pregnancy. J Reprod Med. 1987;32:517-520.

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Renal Hemodynamics

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Renal Hemodynamics
• The glomerular filtration rate (GFR) increases immediately after
conception, resulting in significant hyperfiltration.
Increased GFR in pregnancy % Increase 80%
is mainly influenced by
reduced average oncotic
pressure and increased 50% 50%
ultrafiltration capacity.
Renal plasma flow 30%
increases, due to an
increase in COP and
increased renal vasodilation
of the afferent and arteriole
arterioles, however,
glomerular BP remains
normal. 1st Trimester 2nd Trimester 3rd Trimester

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Renal Hemodynamics

• RPF falls toward nonpregnant levels in the third trimester,

whereas GFR continues to be elevated, resulting in an increased
filtration fraction.

• All these values normalize 4–6 weeks after delivery.

Odutayo A, Hladunewich M. Obstetric nephrology: renal hemodynamic and metabolic physiology in normal pregnancy. Clin J Am Soc
Nephrol. 2012; 7:2073–2080.

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Renal Hemodynamics

Glomerular filtration
dynamic determinants:

ΔP is the hydraulic pressure

gradient between the glomerular
capillary and Bowman’s capsule

πGC is the mean oncotic pressure

in the glomerular capillary

Kf is the glomerular ultrafiltration

coefficient, the product of the
surface area available for
filtration and the permeability of
the filtration membrane.

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Renal Hemodynamics

Tubuloglomerular Feedback

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Renal Hemodynamics

Increased ΔP and Kf, as well

as reduced πGC have all been
described to contribute, at
different stages and to
different degrees, to the high
GFR in pregnancy.

Oncotic pressure is
substantially decreased
P because of expansion of the
plasma volume.

Kf may increase due to

changes in the surface area
for filtration and the
hydraulic permeability.

Tubuloglomerular Feedback

Deng A, Baylis C. Glomerular hemodynamic responses to pregnancy in rats with severe reduction of renal mass. Kidney Int. 1995;
48(1):39–44.
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Renal Hemodynamics

Sustained increase in GFR

postpartum is due to either a
rise in ΔP up to 16%, and 50%
increase in Kf.

On the other hand, several

studies were not able to find
evidence of increased ΔP.

Hladunewich MA, Lafayette RA, Gerby GC,

et al. The dynamics of glomerular filtration
in the puerperium. Am J Physiol Ren
Physiol. 2004; 286(3):F496–F503.

Baylis C. The mechanism of the increase in

Tubuloglomerular Feedback glomerular filtration rate in the twelve-day
pregnant rat. J Physiol. 1980; 305(1):405–
414.

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Renal Hemodynamics

Increased RPF increases GFR

even without any changes to
ΔP or Kf, and contributes in
decreasing glomerular
oncotic pressure

Tubuloglomerular Feedback

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Renal Hemodynamics

Tubuloglomerular feedback,
(normally counteract the rise
in GFR) , is reset to allow for
higher GFR.

Baylis C. The mechanism of the increase in

Tubuloglomerular Feedback glomerular filtration rate in the twelve-day
pregnant rat. J Physiol. 1980; 305(1):405–
414.

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Renal Hemodynamics

• This significant increase in GFR leads to decrease in serum

creatinine to 0.4 - 0.5 mg/dl,

• Blood urea nitrogen (BUN) falls to 8 - 10 mg/dl.

• MDRD and CKD-EPI formulae tend to underestimate GFR and

cannot be used in pregnancy.

• Assessment of renal function in pregnancy is therefore limited to

serial monitoring of serum creatinine level.

Smith, M. C., Moran, P., Ward, M. K. & Davison, J. M. Assessment of glomerular filtration rate during pregnancy using the MDRD formula.
BJOG 115, 109–112 (2008).
Alper, A. B. et al. Performance of estimated glomerular filtration rate prediction equations in preeclamptic patients. Am. J. Perinatol. 28,
425–430 (2010).
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Renal Hemodynamics

• Relaxin (released from the corpus luteum), nitric oxide (NO) and
progesterone mediate the renal vasodilation and glomerular
hyperfiltration.

• Relaxin mediates its effects via matrix metalloproteinase-2 and

endothelin receptor type B leading to NO-dependent
vasodilation.

Jeyabalan, A. et al. Essential role for vascular gelatinase activity in relaxin-induced renal vasodilation, hyperfiltration, and reduced
myogenic reactivity of small arteries. Circ. Res. 93, 1249–1257 (2003).

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Renal Hemodynamics

Relaxin administration to male and nonpregnant female rats

produced physiologic changes that mimicked normal pregnancy,

 Decrease in systemic vascular resistance

 Significant increases in effective RPF and GFR.

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Renal Hemodynamics

Elimination of relaxin, via administration of relaxin-specific

monoclonal antibodies or ovariectomy, prevented the characteristic
renal hemodynamic changes in pregnant rats.

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Renal Hemodynamics

• Pregnant rats received the nitric oxide synthase inhibitor,

nitro-L-arginine methyl ester (L-NAME),
• Acute or chronic inhibition of NO synthase, led to abolishment
of the glomerular hyperfiltration in pregnancy.
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Renal Hemodynamics

• Both relaxin and NO may also factor in the development of

glomerular hyperfiltration in human pregnancy, but the existing
data are less conclusive.

Irrespective of gender, short-term administration of recombinant

relaxin produced increase in RPF 47%, but no changes were noted
in GFR.

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Renal Hemodynamics

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Renal Tubular Function

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Renal Tubular Function

The renal handling Glucose Calcium

of a number of
solutes is altered in
normal pregnancy.
Uric
Acid Protein
Increments in
excretion of some
substances, are
limited by Bicarbonate Amino Acids
increases in tubular & Vitamins
reabsorption.

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Renal Tubular Function

 Glucose:
• Glycosuria frequently occurs during pregnancy, and reflects
reduced tubular reabsorption without a metabolic disturbance.

• It is caused by:
 a decrease in The maximum transport capacity (Tmax) mostly in
the proximal tubule, and

 the inability of the renal tubules to cope with the increased

filtered glucose load.

Baylis C, Davison JM. The renal system. In: Chamberlain G, Broughton Pipkin F, eds. Clinical Physiology in Obstetrics. 3rd
ed. Oxford: Blackwell Science; 1998:263-307.

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Renal Tubular Function

 Calcium:
• Calcium excretion increases 2-3 times during pregnancy because
of the increased filtered load.

• Simultaneous increases in urinary acidic glycoproteins,

magnesium, citrate, and nephrocalcin serve to inhibit calcium
oxalate calculi formation.

Gambaro, G. et al. Increased urinary excretion of glycosaminoglycans in pregnancy and in diabetes mellitus: a protective factor against
nephrolithiasis. Nephron 50, 62–63 (1988).
Butler, E. L., Cox, S. M., Eberts, E. G. & Cunningham, F. G. Symptomatic nephrolithiasis complicating pregnancy. Obstet. Gynecol. 96, 753–
756 (2000).

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Renal Tubular Function

 Uric Acid:
• Reabsorption of uric acid is reduced in pregnancy.

• Serum uric acid is decreased in the first trimester by about 25%

(UA= 2-3 mg/dl), and then gradually increase as pregnancy
progresses.

• High renal clearance is necessary to clear the increased

production of fetal and placental growth.

van Buul EJ, Steegers EA, Jongsma HW, Eskes TK, Thomas CM, Hein PR: Haematological and biochemical profile of uncomplicated
pregnancy in nulliparous women; a longitudinal study. Neth J Med 46: 73–85, 1995

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Renal Tubular Function

 Uric Acid:
• Uric acid has been noted to be elevated in pregnancies
complicated by pre-eclampsia,

 due to decreased renal clearance secondary to glomerular

endotheliosis

 increased production caused by trophoblast breakdown.

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Renal Tubular Function

 Bicarbonate:
• Hyperventilation in pregnancy causes a mild chronic respiratory
alkalosis

• with secondary compensatory decrease in serum HCO3

concentration and increased its excretion.

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Renal Tubular Function

 Amino acids & Vitamins:

• Urinary excretion of most amino acids increases in pregnancy, as
a result of decreased tubular reabsorption.

• Nicotinic acid, ascorbic acid, and folic acid are all excreted in
increased amounts during pregnancy.

Hytten FE, Cheyne GA. The aminoaciduria of pregnancy. J Obstet Gynaecol Br Commonw. 1972;79:424-432.

Lindheimer MD, Davison JM, Katz AI. The kidney and hypertension in pregnancy: Twenty exciting years. Semin Nephrol. 2001;21:173-189.

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Renal Tubular Function

 Protein:
• Significant proteinuria should not only be attributed to the
hyperfiltration that occurs during normal pregnancy.

• Impaired tubular reabsorption also contributes to the generation

of proteinuria, which is notable after 20 weeks gestation.

• The protein content in urine is mostly Tamm-Horsfall, with a small

amount of albumin and other circulating proteins.

Lindheimer MD, Kanter D: Interpreting abnormal proteinuria in pregnancy: The need for a more pathophysiological
approach. Obstet Gynecol 115: 365–375, 2010

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Renal Tubular Function

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Impact on Fetal Programming

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Impact on Fetal Programming

• Women with normal pregnancy who have suboptimal increases

in plasma volume are more likely to have fetal growth restriction
and preterm delivery.

• This can program the offspring for adult life increased risk of
hypertension, other cardiovascular events, diabetes,
hypercholesterolemia, and chronic kidney disease caused by
reduction in nephron number.

Zandi-Nejad K, Luyckx VA, Brenner BM. Adult hypertension and kidney disease: The role of fetal programming. Hypertension.
2006;47:502-508.

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Renal Changes during Pregnancy

Take Home Message

• The precise orchestration of hemodynamic changes and balance

of fluid and electrolytes are essential to the development and
maintenance of a successful pregnancy for mother and child.

• The volume sensing and regulatory systems are dramatically

readjusted throughout pregnancy to accommodate and maintain
the volume expansion.

• The sum effect of volume expansion, increases in COP and pulse

rate, reduced SVR, and blood pressure is renal vasodilation and
increased RPF and GFR.

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Renal Changes during Pregnancy

Take Home Message

Changes in Numbers
• Knowledge of the anatomical, Kidney Size 1 – 1.5 cm
physiological and biochemical Kidney volume 30%
values of these alterations Osmolality 270 mosm/kg
permits earlier detection and Blood pressure 5 – 10 mmHg
facilitates management of renal RBF 80%
diseases and hypertension GFR 50%
during pregnancy. S. Creatinine 0.4 – 0.5 mg/dl
BUN 8 – 10 mg/dl
Uric Acid 2 – 3 mg/dl
Hb 10.5 – 11 g/dl
Hct 33%
Sodium 4 – 5 mmol/l
Potassium 0.25 mmol/l
Bicarbonate 20 mmol/l
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Thank You

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