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Renal Changes during Pregnancy

Renal changes during pregnancy include: 1. Structural changes such as increased kidney size and volume due to vascular and interstitial fluid changes. 2. Systemic changes including resetting of osmoregulation and volume regulation set points to accommodate increased plasma volume. Hormonal changes like increased progesterone, relaxin, and erythropoietin also impact renal function. 3. Renal hemodynamic changes with glomerular filtration rate increasing up to 50% in the first trimester due to reduced oncotic pressure and increased ultrafiltration capacity, remaining elevated through pregnancy.

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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
• Substantial structural and functional changes take place as a maternal adaptation to normal pregnancy. • A state of new temporary norm, due to alterations in: Renal Changes during Pregnancy ESNT 2020 • Distinguish normal from compromised pregnancies.
Structural Changes ESNT 2020
Structural Changes • Increase in renal bipolar diameter. ESNT 2020 1st Trimester 2nd Trimester 3rd TrimesterNon pregnant Postpartum 1-1.5 cm By 26th week 3-6 months
ESNT 2020 Structural Changes Kidney volume enlarges by about 30% because of increments in both vascular and interstitial fluid compartments. Physiologic hydronephrosis Smooth muscle– relaxing effect of progesterone Mechanical compression by the enlarging uterus 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. Urinary stasis predisposes pregnant women with asymptomatic bacteriuria to develop acute pyelonephritis.
ESNT 2020 Structural Changes The right ureter crosses the iliac and ovarian vessels at a more acute angle than left ureter before entering the pelvis Intravenous urogram at 36 weeks’ gestation
ESNT 2020 Structural Changes Threshold for development: 20 weeks Maximal incidence: 28 weeks Overall incidence: 63%
• 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). ESNT 2020 Structural Changes
ESNT 2020 Structural Changes an increase of 150 mg/g in singleton pregnancies and 220 mg/g in twin pregnancies at 34–38 weeks of gestation.
• 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. ESNT 2020 Structural Changes
ESNT 2020 Structural Changes soluble fms-like tyrosine kinase 1 Placental growth factor VEGF • 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 VEC
ESNT 2020 Structural Changes
ESNT 2020 Structural Changes
Systemic Changes ESNT 2020
Systemic Changes ESNT 2020 Osmoregulation Volume Regulation Endocrinal Changes Electrolytes Systemic Hemodynamics
 Osmoregulation • Early in pregnancy, plasma osmolality decreases ESNT 2020 Systemic Changes 10 mOsm/kg below the nonpregnant norm because of a reduction in serum sodium and associated anions. The osmotic threshold for antidiuretic hormone (ADH) release The threshold for thirst to recognize the reduced plasma osmolality and expanded plasma volume as normal. Plasma volume status (a nonosmotic determinant of ADH release) is also reset
 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. ESNT 2020 Systemic Changes Lindheimer MD, Davison JM. Osmoregulation, the secretion of arginine vasopressin and its metabolism during pregnancy. Eur J Endocrinol. 1995;132:133-143. The metabolic clearance rate of ADH has increased four times at week 10 and through midpregnancy because of the release of enzyme vasopressinase from the placenta. Plasma ADH concentrations are usually kept normal in pregnancy because of increased secretion.
 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. ESNT 2020 Systemic Changes 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.
 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. ESNT 2020 Systemic Changes
ESNT 2020 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. ESNT 2020 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. ESNT 2020 Systemic Changes 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.
 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. ESNT 2020 Systemic Changes 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.
 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. ESNT 2020 Systemic Changes 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.
 Endocrinal Changes: ESNT 2020 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. ESNT 2020 Systemic Changes 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).
 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. ESNT 2020 Systemic Changes
 Systemic Hemodynamics ESNT 2020 Systemic Changes 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. 1st Trimester 2nd Trimester 3rd Trimester 50 40 30 20 10 5th 8th 26th Heart Rate Stroke Volume Cardiac output significantly increases by the 5th gestational week % Increase
 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. ESNT 2020 Systemic Changes 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.
 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. ESNT 2020 Systemic Changes 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.
 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. ESNT 2020 Systemic Changes
 Electrolytes Sodium: Retention of sodium is a complex interplay of natriuretic and antinatriuretic factors, ESNT 2020 Systemic Changes 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
 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. ESNT 2020 Systemic Changes Davison JM, Lindheimer MD: Volume homeostasis and osmoregulation in human pregnancy. Baillieres Clin Endocrinol Metab 3: 451–472, 1989
 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. ESNT 2020 Systemic Changes Lindheimer MD, Richardson DA, Ehrlich EN, Katz AI. Potassium homeostasis in pregnancy. J Reprod Med. 1987;32:517-520.
Renal Hemodynamics ESNT 2020
Renal Hemodynamics • The glomerular filtration rate (GFR) increases immediately after conception, resulting in significant hyperfiltration. ESNT 2020 1st Trimester 2nd Trimester 3rd Trimester 50% 30% 80% 50% % IncreaseIncreased GFR in pregnancy is mainly influenced by reduced average oncotic pressure and increased ultrafiltration capacity. Renal plasma flow increases, due to an increase in COP and increased renal vasodilation of the afferent and arteriole arterioles, however, glomerular BP remains normal.
• 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. ESNT 2020 Renal Hemodynamics Odutayo A, Hladunewich M. Obstetric nephrology: renal hemodynamic and metabolic physiology in normal pregnancy. Clin J Am Soc Nephrol. 2012; 7:2073–2080.
ESNT 2020 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.
ESNT 2020 Renal Hemodynamics Tubuloglomerular Feedback P
ESNT 2020 Renal Hemodynamics Tubuloglomerular Feedback P 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 because of expansion of the plasma volume. Kf may increase due to changes in the surface area for filtration and the hydraulic permeability. Deng A, Baylis C. Glomerular hemodynamic responses to pregnancy in rats with severe reduction of renal mass. Kidney Int. 1995; 48(1):39–44.
ESNT 2020 Renal Hemodynamics Tubuloglomerular Feedback P 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 glomerular filtration rate in the twelve-day pregnant rat. J Physiol. 1980; 305(1):405– 414.
ESNT 2020 Renal Hemodynamics Tubuloglomerular Feedback P Increased RPF increases GFR even without any changes to ΔP or Kf, and contributes in decreasing glomerular oncotic pressure
ESNT 2020 Renal Hemodynamics Tubuloglomerular Feedback P Tubuloglomerular feedback, (normally counteract the rise in GFR) , is reset to allow for higher GFR. Baylis C. The mechanism of the increase in glomerular filtration rate in the twelve-day pregnant rat. J Physiol. 1980; 305(1):405– 414.
• 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. ESNT 2020 Renal Hemodynamics 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).
• 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. ESNT 2020 Renal Hemodynamics 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).
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. ESNT 2020 Renal Hemodynamics
Elimination of relaxin, via administration of relaxin-specific monoclonal antibodies or ovariectomy, prevented the characteristic renal hemodynamic changes in pregnant rats. ESNT 2020 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. ESNT 2020 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. ESNT 2020 Renal Hemodynamics Irrespective of gender, short-term administration of recombinant relaxin produced increase in RPF 47%, but no changes were noted in GFR.
ESNT 2020 Renal Hemodynamics
Renal Tubular Function ESNT 2020
Renal Tubular Function ESNT 2020 Glucose Calcium Amino Acids & Vitamins Bicarbonate Uric Acid Protein The renal handling of a number of solutes is altered in normal pregnancy. Increments in excretion of some substances, are limited by increases in tubular reabsorption.
 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. ESNT 2020 Renal Tubular Function 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.
 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. ESNT 2020 Renal Tubular Function 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).
 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. ESNT 2020 Renal Tubular Function 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
 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. ESNT 2020 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. ESNT 2020 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. ESNT 2020 Renal Tubular Function 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.
 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. ESNT 2020 Renal Tubular Function Lindheimer MD, Kanter D: Interpreting abnormal proteinuria in pregnancy: The need for a more pathophysiological approach. Obstet Gynecol 115: 365–375, 2010
ESNT 2020 Renal Tubular Function
Impact on Fetal Programming ESNT 2020
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. ESNT 2020 Zandi-Nejad K, Luyckx VA, Brenner BM. Adult hypertension and kidney disease: The role of fetal programming. Hypertension. 2006;47:502-508.
• 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. Renal Changes during Pregnancy ESNT 2020 Take Home Message
Renal Changes during Pregnancy ESNT 2020 Take Home Message Changes in Numbers Kidney Size Kidney volume 1 – 1.5 cm 30% Osmolality 270 mosm/kg Blood pressure 5 – 10 mmHg RBF 80% GFR 50% 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 • Knowledge of the anatomical, physiological and biochemical values of these alterations permits earlier detection and facilitates management of renal diseases and hypertension during pregnancy.
ESNT 2020 Thank You

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Renal Changes during Pregnancy

  • 1.
    Renal Changes during Pregnancy WaleedElrefaey MD Lecturer of Internal Medicine Nephrology Division Faculty of Medicine, Tanta University
  • 2.
    AGENDA • Structural Changes •Systemic Changes:  Osmoregulation  Volume Regulation  Endocrinal Changes  Systemic Hemodynamics  Electrolytes • Renal Hemodynamics • Renal Tubular Function • Impact on Fetal Programming
  • 3.
    • Substantial structuraland functional changes take place as a maternal adaptation to normal pregnancy. • A state of new temporary norm, due to alterations in: Renal Changes during Pregnancy ESNT 2020 • Distinguish normal from compromised pregnancies.
  • 4.
  • 5.
    Structural Changes • Increasein renal bipolar diameter. ESNT 2020 1st Trimester 2nd Trimester 3rd TrimesterNon pregnant Postpartum 1-1.5 cm By 26th week 3-6 months
  • 6.
    ESNT 2020 Structural Changes Kidneyvolume enlarges by about 30% because of increments in both vascular and interstitial fluid compartments. Physiologic hydronephrosis Smooth muscle– relaxing effect of progesterone Mechanical compression by the enlarging uterus 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. Urinary stasis predisposes pregnant women with asymptomatic bacteriuria to develop acute pyelonephritis.
  • 7.
    ESNT 2020 Structural Changes Theright ureter crosses the iliac and ovarian vessels at a more acute angle than left ureter before entering the pelvis Intravenous urogram at 36 weeks’ gestation
  • 8.
    ESNT 2020 Structural Changes Thresholdfor development: 20 weeks Maximal incidence: 28 weeks Overall incidence: 63%
  • 9.
    • 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). ESNT 2020 Structural Changes
  • 10.
    ESNT 2020 Structural Changes anincrease of 150 mg/g in singleton pregnancies and 220 mg/g in twin pregnancies at 34–38 weeks of gestation.
  • 11.
    • 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. ESNT 2020 Structural Changes
  • 12.
    ESNT 2020 Structural Changes solublefms-like tyrosine kinase 1 Placental growth factor VEGF • 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 VEC
  • 13.
  • 14.
  • 15.
  • 16.
    Systemic Changes ESNT 2020 OsmoregulationVolume Regulation Endocrinal Changes Electrolytes Systemic Hemodynamics
  • 17.
     Osmoregulation • Earlyin pregnancy, plasma osmolality decreases ESNT 2020 Systemic Changes 10 mOsm/kg below the nonpregnant norm because of a reduction in serum sodium and associated anions. The osmotic threshold for antidiuretic hormone (ADH) release The threshold for thirst to recognize the reduced plasma osmolality and expanded plasma volume as normal. Plasma volume status (a nonosmotic determinant of ADH release) is also reset
  • 18.
     Osmoregulation • Humanchorionic gonadotropin (which stimulates the release of ovarian relaxin) may have a role in this reduction of the osmotic threshold for ADH release. ESNT 2020 Systemic Changes Lindheimer MD, Davison JM. Osmoregulation, the secretion of arginine vasopressin and its metabolism during pregnancy. Eur J Endocrinol. 1995;132:133-143. The metabolic clearance rate of ADH has increased four times at week 10 and through midpregnancy because of the release of enzyme vasopressinase from the placenta. Plasma ADH concentrations are usually kept normal in pregnancy because of increased secretion.
  • 19.
     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. ESNT 2020 Systemic Changes 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.
  • 20.
     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. ESNT 2020 Systemic Changes
  • 21.
  • 22.
     Endocrinal Changes: Physiologicalchanges 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. ESNT 2020 Systemic Changes
  • 23.
     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. ESNT 2020 Systemic Changes 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.
  • 24.
     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. ESNT 2020 Systemic Changes 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.
  • 25.
     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. ESNT 2020 Systemic Changes 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.
  • 26.
     Endocrinal Changes: ESNT2020 Systemic Changes
  • 27.
     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. ESNT 2020 Systemic Changes 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).
  • 28.
     Endocrinal Changes: VitaminD • 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. ESNT 2020 Systemic Changes
  • 29.
     Systemic Hemodynamics ESNT2020 Systemic Changes 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. 1st Trimester 2nd Trimester 3rd Trimester 50 40 30 20 10 5th 8th 26th Heart Rate Stroke Volume Cardiac output significantly increases by the 5th gestational week % Increase
  • 30.
     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. ESNT 2020 Systemic Changes 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.
  • 31.
     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. ESNT 2020 Systemic Changes 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.
  • 32.
     Electrolytes Pregnancy ischaracterized 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. ESNT 2020 Systemic Changes
  • 33.
     Electrolytes Sodium: Retention ofsodium is a complex interplay of natriuretic and antinatriuretic factors, ESNT 2020 Systemic Changes 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
  • 34.
     Electrolytes Sodium: • Progesteroneattenuates 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. ESNT 2020 Systemic Changes Davison JM, Lindheimer MD: Volume homeostasis and osmoregulation in human pregnancy. Baillieres Clin Endocrinol Metab 3: 451–472, 1989
  • 35.
     Electrolytes Potassium: • Totalbody 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. ESNT 2020 Systemic Changes Lindheimer MD, Richardson DA, Ehrlich EN, Katz AI. Potassium homeostasis in pregnancy. J Reprod Med. 1987;32:517-520.
  • 36.
  • 37.
    Renal Hemodynamics • Theglomerular filtration rate (GFR) increases immediately after conception, resulting in significant hyperfiltration. ESNT 2020 1st Trimester 2nd Trimester 3rd Trimester 50% 30% 80% 50% % IncreaseIncreased GFR in pregnancy is mainly influenced by reduced average oncotic pressure and increased ultrafiltration capacity. Renal plasma flow increases, due to an increase in COP and increased renal vasodilation of the afferent and arteriole arterioles, however, glomerular BP remains normal.
  • 38.
    • RPF fallstoward 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. ESNT 2020 Renal Hemodynamics Odutayo A, Hladunewich M. Obstetric nephrology: renal hemodynamic and metabolic physiology in normal pregnancy. Clin J Am Soc Nephrol. 2012; 7:2073–2080.
  • 39.
    ESNT 2020 Renal Hemodynamics Glomerularfiltration 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.
  • 40.
  • 41.
    ESNT 2020 Renal Hemodynamics TubuloglomerularFeedback P 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 because of expansion of the plasma volume. Kf may increase due to changes in the surface area for filtration and the hydraulic permeability. Deng A, Baylis C. Glomerular hemodynamic responses to pregnancy in rats with severe reduction of renal mass. Kidney Int. 1995; 48(1):39–44.
  • 42.
    ESNT 2020 Renal Hemodynamics TubuloglomerularFeedback P 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 glomerular filtration rate in the twelve-day pregnant rat. J Physiol. 1980; 305(1):405– 414.
  • 43.
    ESNT 2020 Renal Hemodynamics TubuloglomerularFeedback P Increased RPF increases GFR even without any changes to ΔP or Kf, and contributes in decreasing glomerular oncotic pressure
  • 44.
    ESNT 2020 Renal Hemodynamics TubuloglomerularFeedback P Tubuloglomerular feedback, (normally counteract the rise in GFR) , is reset to allow for higher GFR. Baylis C. The mechanism of the increase in glomerular filtration rate in the twelve-day pregnant rat. J Physiol. 1980; 305(1):405– 414.
  • 45.
    • This significantincrease 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. ESNT 2020 Renal Hemodynamics 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).
  • 46.
    • Relaxin (releasedfrom 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. ESNT 2020 Renal Hemodynamics 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).
  • 47.
    Relaxin administration tomale and nonpregnant female rats produced physiologic changes that mimicked normal pregnancy,  Decrease in systemic vascular resistance  Significant increases in effective RPF and GFR. ESNT 2020 Renal Hemodynamics
  • 48.
    Elimination of relaxin,via administration of relaxin-specific monoclonal antibodies or ovariectomy, prevented the characteristic renal hemodynamic changes in pregnant rats. ESNT 2020 Renal Hemodynamics
  • 49.
    • Pregnant ratsreceived 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. ESNT 2020 Renal Hemodynamics
  • 50.
    • Both relaxinand NO may also factor in the development of glomerular hyperfiltration in human pregnancy, but the existing data are less conclusive. ESNT 2020 Renal Hemodynamics Irrespective of gender, short-term administration of recombinant relaxin produced increase in RPF 47%, but no changes were noted in GFR.
  • 51.
  • 52.
  • 53.
    Renal Tubular Function ESNT2020 Glucose Calcium Amino Acids & Vitamins Bicarbonate Uric Acid Protein The renal handling of a number of solutes is altered in normal pregnancy. Increments in excretion of some substances, are limited by increases in tubular reabsorption.
  • 54.
     Glucose: • Glycosuriafrequently 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. ESNT 2020 Renal Tubular Function 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.
  • 55.
     Calcium: • Calciumexcretion 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. ESNT 2020 Renal Tubular Function 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).
  • 56.
     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. ESNT 2020 Renal Tubular Function 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
  • 57.
     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. ESNT 2020 Renal Tubular Function
  • 58.
     Bicarbonate: • Hyperventilationin pregnancy causes a mild chronic respiratory alkalosis • with secondary compensatory decrease in serum HCO3 concentration and increased its excretion. ESNT 2020 Renal Tubular Function
  • 59.
     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. ESNT 2020 Renal Tubular Function 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.
  • 60.
     Protein: • Significantproteinuria 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. ESNT 2020 Renal Tubular Function Lindheimer MD, Kanter D: Interpreting abnormal proteinuria in pregnancy: The need for a more pathophysiological approach. Obstet Gynecol 115: 365–375, 2010
  • 61.
  • 62.
    Impact on FetalProgramming ESNT 2020
  • 63.
    Impact on FetalProgramming • 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. ESNT 2020 Zandi-Nejad K, Luyckx VA, Brenner BM. Adult hypertension and kidney disease: The role of fetal programming. Hypertension. 2006;47:502-508.
  • 64.
    • The preciseorchestration 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. Renal Changes during Pregnancy ESNT 2020 Take Home Message
  • 65.
    Renal Changes duringPregnancy ESNT 2020 Take Home Message Changes in Numbers Kidney Size Kidney volume 1 – 1.5 cm 30% Osmolality 270 mosm/kg Blood pressure 5 – 10 mmHg RBF 80% GFR 50% 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 • Knowledge of the anatomical, physiological and biochemical values of these alterations permits earlier detection and facilitates management of renal diseases and hypertension during pregnancy.
  • 66.