Renal hemodynamics in normal pregnancy and preeclampsia

In 1951, Bucht's studies suggested that renal blood flow increased substantially in human pregnancy, and this was confirmed by subsequent investigators, but methodological variation resulted in considerable controversy regarding the timing and magnitude of the increment. The ''best'' studies were those where the same women were studied serially throughout pregnancy as well as prepregnancy and/or postnatally under standardized conditions with glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) determined by para-aminohippurate (PAH) and inulin clearances, respectively (Assali et al., 1959; Chapman et al., 1997; de Alvarez, 1958; Dunlop, 1981; Milne et al., 2002; Roberts et al., 1996; Sims and Krantz, 1958).

From these studies it is acknowledged that ERPF and GFR increase markedly in the first part of pregnancy by 50—85% and 40—60%, respectively. The consensus is that this enhanced performance is maintained throughout pregnancy, possibly with a reduction in ERPF in late pregnancy (Ezimokhai etal., 1981). From 24h creatinine clearance as well as inulin measurements it is evident that GFR is increased in the luteal phase of the menstrual cycle and still further by 2 weeks (25%) and 6 weeks (41%) gestation (Chapman etal., 1997; Davison and Noble, 1981).

Overall GFR is determined by the number of functioning nephrons and the rate of filtration in each one. Each human kidney has approximately 1,000,000 glomeruli and it is believed that in the healthy kidney all the glomeruli are functioning all of the time. Variation in overall renal function is therefore a result of regulation of the filtration rate within individual glomeruli. Variables which influence the single nephron glomerular filtration rate (SNGFR) will necessarily modify renal function as a whole.

Four physical parameters have been identified which determine glomerular filtration rate (Figure 23.3):

• the trans-capillary hydrostatic pressure gradient;

• the characteristics of the membrane;

• the characteristics of the solutes; and

• glomerular hemodynamics.

Animal model studies allow direct measurement of renal parameters using micropuncture techniques and in pregnancy it seems likely that the gestational increases in GFR are a consequence of renal vasodilatation (Baylis, 1987; Conrad, 1984, 1987), with both afferent and efferent arterioles equally affected, thus increasing GFR without concomitant elevation in glomerular pressure (AP) (Baylis, 1980, 1994). Although such invasive studies are impossible in humans, mathematical estimations of the various parameters can be indirectly estimated (Deen et al., 1979) and results using these methods accord with the animal work (Milne etal., 2002; Moran etal., 2003; Roberts etal., 1996). The stimulus for gestational renal vasodilatation remains elusive but there is compelling evidence that it is mediated via nitric oxide pathways (Alexander et al., 1999; Danielson and Conrad, 1995; Gandley et al., 2001). Furthermore, work in rats has demonstrated that the ovarian hormone relaxin plays an important role (Baylis, 1999; Danielson etal., 1999; Novak etal., 2001) and its role in renal adaptation in human pregnancy is currently under investigation. As the failure to establish an appropriate hemodynamic response in early pregnancy can be associated with an increased tendency to develop fetal growth restriction and pre-eclampsia at a later gestation (Duvekot et al., 1995; Easterling et al., 1990), better understanding of the renal adaptation in normal pregnancy could provide further clues about the etiology of the pre-eclamptic process.

A recent review (Lindheimer, 1999) of studies investigating renal hemodynamic changes in pre-eclamptic and normal pregnancies showed that, on average, there is a 32% reduction in GFR and a 24% reduction in ERPF in pre-eclampsia compared to normal pregnancy values (Table 23.1). Although the perpetrator responsible for the reduced blood flow has not been identified, there is probably a selective increase in afferent arteriolar resistance (Baylis and Reckelhoff, 1991), explaining why filtration fraction (FF) is affected to a lesser extent than the other hemodynamic parameters.

Glomerular ultrafiltration, and its individual components, can be interrogated using models which apply theoretical principles of fluid properties to the glomerular vascular bed (Deen et al., 1972, 1979, 1985). The ultrafiltration coefficient Kf represents the product of glomerular hydraulic permeability and filtration surface area and is thus an important determinant of GFR. Studies using both morphometric techniques (Lafayette et al., 1998) and mathematical modeling of neutral dextran clearances (Moran et al., 2003) predict a

40% reduction of Kf in pre-eclampsia compared to normal pregnancy. It is unlikely that the surface area is altered and therefore it has been suggested that the reduction in Kf is a consequence of reduced glomerular hydraulic permeability secondary to impaired structural integrity of the membrane or altered charge selectivity. The relative contribution of the two main determinants of renal function, namely blood flow and glomerular hydraulic permeability, to the reduced GFR seen in pre-eclampsia remains controversial.

Table 23.1. Comparison of renal hemodynamic function in nonpregnant women, normal pregnancy and pregnancy complicated by pre-eclampsia (mean values, summarized from Conrad and Lindheimer (1999) and Moran et al. (2003))

Non- Normal Pre-eclamptic pregnant pregnancy pregnancy

Table 23.1. Comparison of renal hemodynamic function in nonpregnant women, normal pregnancy and pregnancy complicated by pre-eclampsia (mean values, summarized from Conrad and Lindheimer (1999) and Moran et al. (2003))

Non- Normal Pre-eclamptic pregnant pregnancy pregnancy

GFR (ml min"1)

114

133

90

ERPF (ml min"1)

581

649

487

FF (%)

19.5

20.4

18.7

Kf (ml min"1mmHg"1)

8.0

8.9

4.6

Figure 23.3 Physical parameters determining glomerular filtration rate.

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