Slide 1

Good morning I am sorry that I got a virus from Stockholm and during the past night I did not sleep very well but I will try to be ok today.

Slide 2

00.15.825

There are some anatomical changes in the kidney with an increased length and increased weight and increased volume of the kidney up to 30%. This kidney weight increase is due to an increase in water content. In addition, the urinary tract is modified.

Slide 3

00.36.098

Dilatation of urinary tract at the level of the collecting system, calices, renal pelves and  ureters. There is a dilatation that is occurring before the uterus is enlarged and ureteral catheterisation fails to reverse dilation. This increase in dilation before the uterus is enlarged is probably due to modification of the endocrine system during pregnancy. However from the second trimester there is an increase also of the pressure that may explain why there is an increased ureteral pressure and also enlargement.

Slide 4

01.16.809

The main change that we are seeing in the circulatory in pregnancy is an increase in total blood volume mostly due to an increase in the plasma volume. But there is also an increase in red blood cells volume and this is increasing along the pregnancy from week 8 to week 40. Immediately after delivery very quickly all is returning to normal.

Slide 5

01.43.750

This is the reason why we can see an increase in the stroke volume that it is increasing by 40, 45, 50% during pregnancy and this is not only due to the heart rate that is increasing but because of the change in the blood volume.

Slide 6

02.04.632

Even with an increase in blood volume, even with an increase in cardiac output we have a decrease of the blood pressure during pregnancy. This is due to the vasodilatation, peripheral vasodilatation and a decrease in the vasoconstriction. This decrease of blood pressure in particular is ill after week 12-15 and the blood pressure is between 100-105 mmHg systolic and 50-65 mmHg diastolic blood pressure.

Slide 7

02.44.183

In the meantime the physiological changes we can see that there is an increase in GFR and we will see why after that and in the blood we can see there is a decrease of urea, creatinine, uric acid, albumin, total protein but also osmolarity and sodium. That means that the plasma sodium may decrease by 5 mg/L during pregnancy.

Slide 8

03.14.804

In addition there is the occurrence of alkalosis. The progesterone stimulates the sensitivity of respiratory centre to CO2, increases the minute ventilation, decreases the pCO2 and increases the pH. These changes associated to a bicarbonate between 18-22 mmol/L is very important to control the elimination of the protons produced by the foetal metabolism. In addition, there is a mild increase in pO2. Another thing that is very important to note that even in presence of a decreased bicarbonate and a tendency of increased pH there is a normal urinary acidification. The titrable acid and ammonium excretion are similar to those seen and even better  than those found in non-pregnant women when there is an acute or chronic administration of ammonium chloride.

Slide 9

04.17.545

In addition, the increase in GFR that we can see and we saw this before, this is 4-5 works that have been done with inulin clearance is due mainly to an increase in renal plasma flow. The increase in GFR remains increased up to the end of the pregnancy with a mild diminution in some cases but in most of the experiments and investigations that have been done there is a mild decrease of renal plasma flow.

Slide 10

04.50.594

Considering these changes in human pregnancy we can see that the mean arterial pressure is decreasing, the cardiac output is increasing, the blood volume is increasing, the plasma renin activity is increasing very much in presence of high GFR and high renal plasma flow. The increase of renin is associated with an increase in angiotensin II, aldosterone and so on.

Slide 11

05.19.219

In fact we can summarise that in a normal pregnancy the blood pressure decreases, the blood volume increases, the cardiac output is elevated, the peripheral resistance is diminished, renal blood flow and GFR are increased.

Slide 12

05.35.049

Now in presence of these changes we have an increase in plasma renal activity, an increase in aldosterone, an increase in prostacyclin, thromboxane and also in nitric oxide productions. These changes explain the increase in nitric oxide, prostacyclin and so on while there is a decrease in peripheral resistance and we will see in more detail later.

Slide 13

06.00.766

Considering the glomerular pressure we can see that even with an increase in GFR and an increase in renal plasma flow there is no change in glomerular pressure.

Slide 14

06.13.874

And there are no effects in the long term of the effect of hyperfiltration as there is an increase in glomerular plasma flow that induces and increase in single nephron GFR, a diminution of the afferent and efferent arteriolar resistance and the constant glomerular capillary pressure. This is also demonstrated probably in human pregnancy. Therefore there is a hyperfiltration but without high glomerular perfusion pressure and no deleterious effect of this hyperfiltration.

Slide 15

06.50.075

The clinical consequences in the kidney cardiac world is that urea is decreasing up to 15, 16, 18 mg/dL and the creatinine may decrease up to 0. 5 mg/dL. Obviously when there are values that maybe considered to be normal in normal conditions, the increase of urea up to 20-30 of creatinine up to 0.8 may be considered to be abnormal and merit to do further investigations. To be noted that in presence of hyperfiltration there is a normal response to intravenous aminoacids load that means that there is a functional reserve which remains normal.

Slide 16

07.38.642

The ureic acid clearance is also elevated and the blood uric acid level is low 2-3 mg/dL in normal pregnancy. This remains a very sensitive element to diagnose the beginning of renal dysfunction during pregnancy, particularly when pregnancy is suspected. In addition, about 50% of women has glycosuria and this is due to the fact that the fractional reabsorption of glucose is diminished during pregnancy. The other point that is worth remembering is why sodium protein albumin has decreased. There is a lower osmotic set point that induces also an osmotic threshold for stimulation of ADH release and thirst mediated by  hCG and there is a reason why there is a decrease of plasma osmolality to 8-10 mosm/kg diminution. The lower point of this osmolality is seen from week 10. To be noted also that there is an increased aquaporin 2 expression in the collecting tubule and what is important to note is that vasopressinase activity is four times more elevated and this increases the metabolic clearance of AVP. This may explain why in some patients we can see changes of diabetes insipidus due to the increased metabolic rate of AVP.

Slide 17

09.17.109

Considering the change and increase in body weight we can see that the increase is about 12-13 kg during pregnancy. There is an increase of almost 1.8 kg in the amniotic fluid. We have an increase in the blood that is increasing by 1.5 kg and we can see that the extravascular fluid is also increasing by 1.5 kg. That means there is an increase of fluids that reconsidering this pregnancy is about 4-5 kg.

Slide 18

09.57.685

These changes are due to a modification of the sodium reabsorption. There is a positive sodium retention of 950 mg during the pregnancy and this is due to the balance between the factors that promote retention of sodium like aldosterone, deoxycorticosterone and estrogens that are very much increased during pregnancy but also there is an equilibrium with the factors that induce an increased secretion of sodium such like GFR that is increased, progesterone, prostaglandins and AMP.

Slide 19

10.43.815

In any way the cause of the haemodynamic changes and GFR changes are present in pseudo pregnant rats that means without the presence of pregnancy. The injection of progesterone in women and in animals may change the GFR and plasma flow. However this is very much lower than what we see in pregnancy but the chronic administration of relaxin in non-pregnant rats may induce an increase in cardiac output and arterial compliance in these rats.

Slide 20

11.18.419

Therefore, there is great interest now in the appearance of relaxin. Relaxin is a peptide and hormone that is very similar with 2 chains A and B that may be seen in insulin and insulin growth factors. The bridge between the chains are different.

Slide 21

11.35.075

Relaxin is a hormone, a 6 kD peptide produced by the corpus luteum, rises very early during the gestation and induces the renal vasodilation. Neutralisation of relaxin decreases GFR and we will see this.

Slide 22

11.53.209

The production of relaxin is stimulated by the hCG. It increases GFR and renal plasma flow, it decreases vasoconstriction and it decreases the blood osmolality in non-gravid rodents. It has exactly the same effects that we can see during pregnancy. In using antibodies again relaxin or in doing ovariectomy in gravid rats the expected pregnancy rate had changed in renal function and in blood osmolality do not occur or are even reversible.

Slide 23

12.28.307

That means that relaxin is a main hormone which plays a main role in the development of the manifestations of high cardiac outputs, low osmolality and decreased vasoconstriction, peripheral vasoconstriction. It induces in fact the expression that induces an increased expression of ETB 1 receptor subtype in presence of ET 1-32 it stimulates the nitric oxide activity – and increases the nitric oxide values. This is why relaxin plays a role, it stimulates the vascular gelatinase which increases the production of endothelin 1-32 and the presence was elevated –  and elevated receptors and induced an increased NO release. When you are stopping the NO production there is a diminution of the GFR, renal plasma flow and vascular resistance increasing.

Slide 24

13.33.781

In Angioctin in males and in females, non-pregnant the relaxin in humans of human relaxin we can see there is an increase in cardiac output, in blood volume without changes in blood pressure and without changes in the renal perfusion pressure.

Slide 25

13.56.664

In summary we can see that increased estrogen, progesterone, PGE2 and PGI2 and relaxin and nitric oxide induce the changes that we are observing during pregnancy.

Slide 26

14.09.965

In summary, we can say that there is a high cardiac output and high plasma volume, there is an increased GFR, lower blood levels of urea, creatinine and uric acid, elevation of vasodilator and vasoconstrictor hormones leading finally to a state of low systemic and renal vascular resistance. Decreased blood pressure values and respiratory alkalosis with normal adaptation to acid load, to water and to electrolyte imbalance. Thank you very much.